Heterocyclic derivatives for the treatment of rsv

ABSTRACT

Disclosed herein are compounds and compositions for treating or inhibiting RSV and related members of the pneumovirus and paramyxovirus families such as human metapneumovirus, mumps virus, human parainfluenzaviruses, and Nipah and hendra virus, and methods of treatment or prevention thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No. 16/099,957having a filing date of Nov. 8, 2018, which was a 371 application ofInternational application PCT/US2017/031945 filed on May 10, 2017, whichclaimed the benefit of U.S. Provisional Application Ser. No. 62/333,996,filed May 10, 2016, the disclosures of all said applications beingincorporated herein in their entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

This invention was made with government support under grants HD079327and AI071002 awarded by the National Institutes of Health (NIH). Thegovernment has certain rights in the invention.

FIELD OF THE INVENTION

The invention relates to the use of small molecule therapeutics for thetreatment of respiratory syncytial virus (RSV) and related members ofthe pneumovirus and paramyxovirus family such as human metapneumovirus,mumps virus, human parainfluenzaviruses, and Nipah and hendra virus.

BACKGROUND

Respiratory syncytial virus (RSV) is a member of the paramyxovirusfamily, which consists of mostly highly contagious nonsegmented,negative polarity RNA viruses that spread through the respiratory route.Specifically, RSV is a member of the order Mononegavirales, whichconsists of the non-segmented negative strand RNA viruses in theFamilies Paramyxoviridae, Pneumoviridae; Bunyaviridae, Rhabdoviridae andFiloviridae. RSV of humans (often also termed RSV or HRSV) is a memberof the Pneumoviridae. Based on genetic and antigenic variations in thestructural proteins, RSV is classified into two subgroups, A and B(Mufson, M. et al., J. Gen. Virol. 66:2111-2124). Other members of thePneumovirus family include viruses such as bovine RSV (BRSV), ovine RSV(ORSV), pneumonia virus of mice (PVM), and the human metapneumovirusesamongst others.

In addition to the genome features described above, familycharacteristics include a lipid envelope containing one or moreglycoprotein species considered to be associated with attachment andentry of the host cell. Entry is considered to require a process bywhich the viral envelope fuses with the membrane of the host cell.Fusion of infected cells with, for example, their neighbors, can alsoresult in the formation of fused multinucleate cells known as syncytiain some cases. The fusion process is believed to be glycoproteinmediated and is a feature shared with diverse enveloped viruses in othertaxonomic groups. In the case of the pneumo- and paramyxoviruses,virions characteristically express a fusion glycoprotein (F), whichmediates membrane fusion.

Respiratory syncytial virus (RSV) is the leading cause of acute upperand lower respiratory tract infections (LRTI) in adults, young childrenand infants. Although at risk populations include the hospitalized,elderly and high-risk adults, RSV is primarily considered to be apediatric disease due to the prevalence and severity of unfavorableoutcomes in infants. Acute LRTI infections are a leading cause of globalchildhood mortality and morbidity. Serological evidence indicates thatin the western world approximately 95% of all children have beeninfected with RSV by the age of two and 100% of children have beenexposed by the time they reach adulthood.

RSV disease is thus the leading cause of virus infection-induced deathamong children less than 1 year of age and can be life-threatening tothe elderly and the immunocompromised. Reinfection with RSV can occurthroughout life, but infants born prematurely, or with bronchopulmonarydysplasia or a congenital heart defect, are at highest risk ofdeveloping severe disease. In a typical case, initial RSV infection ofairway epithelia cells is followed by rapid spread from the nasopharynxto the lower airways that can affect respiratory function throughexcessive mucus, necrotic epithelial debris, and inflammatory cellsobstructing the airways.

RSV is a seasonal infectious disease that generally runs from Novemberto March/April in the Northern Hemisphere. In more tropical climates,the annual epidemics are more variable, often coinciding with the wetseason. In most cases the RSV infections will only cause minor upperrespiratory illness with symptoms resembling that of the common cold.However, severe infection with the virus may result in bronchiolitis orpneumonia, which may result in hospitalization or death. Further, sincethe immune response to RSV infection is not protective, RSV infectionsreoccur throughout adulthood. Annual re-infection rates in adults of3-6% have been observed.

RSV infections place a significant burden on the healthcare system. Thisis particularly so in the case of infants such as, for example,immunodeficient infants, which on average spend twice as long inhospital as other patients with an RSV infection (7-8 days compared to3-4 days). Hospitalization of infants with acute RSV-relatedbronchiolitis or RSV-related pneumonia involves supportive caremanagement with oxygen therapy, fluids to prevent dehydration, nasalsuctioning and respiratory support. There is also an economic impactassociated with parents taking time away from work to care for theirchild.

Attempts to develop an effective RSV vaccine have been fruitless thusfar, because the virus is poorly immunogenic overall and neutralizingantibody titers wane quickly after infection. Although ribavirin hasbeen approved for RSV treatment, it has not been widely adopted inclinical use due to efficacy and toxicity issues. The humanizedneutralizing antibody palivizumab is used for immunoprophylaxis ofhigh-risk pediatric patients, but high costs prohibit broad-scaleimplementation.

Accordingly, there remains an urgent and unmet need for new compoundsthat are useful in the treatment and prevention of RSV infections.Small-molecule drug-like therapeutics have high promise to provide anovel avenue towards RSV disease management and prevention. It istherefore an object of the present invention to provide newsmall-molecule therapeutics classes for the treatment of human patientsand other hosts infected with RSV.

SUMMARY

Disclosed herein are compounds, compositions, and methods of inhibitingRSV, or treating or preventing RSV infection in a patient in needthereof. RSV can be inhibited, and RSV infection can be treated orprevented by administering to a patient in need thereof a compositioncontaining an anti-RSV compound of Formula 1:

or a pharmaceutically acceptable salt thereof, wherein

-   X is selected from O, S, or NR⁷;-   z and y are independently selected from an integer from 0-6;-   R¹ and R² are independently selected from R^(a), OR^(a), N(R^(a))₂,    SR^(a), wherein R^(a) is in each case independently selected    hydrogen, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₂₋₈ heterocyclyl, C₆₋₁₂    aryl, C₃₋₁₂ heteroaryl, C₁₋₈ alkyl-C₃₋₈ cycloalkyl, C₁₋₈ alkyl-C₂₋₈    heterocyclyl, C₁₋₈ alkyl-C₆₋₁₂ aryl, and C₁₋₈ alkyl-C₃₋₁₂    heteroaryl; and when N(R^(a))₂ is present,-   R³, R⁴, R⁵, and R⁶ are independently selected from independently    selected from —R^(a), —OR^(a), —N(R^(a))₂, —SR^(a), —SO₂R^(a),    —SO₂N(R^(a))₂; —C(O)R^(a), OC(O)R^(a), —COOR^(a), —C(O)N(R^(a))₂,    —OC(O)N(R^(a))₂, —N(R^(a))C(O), —N(R^(a))C(O)N(R^(a))₂, —F, —Cl,    —Br, —I, —CN, —NO₂; wherein R^(a) is independently selected from the    definitions given above,-   R⁷, when present, is R^(a), C(O)R^(a), SO₂R^(a), COOR^(a),    C(O)N(R^(a))₂,    wherein either of R³ and R⁴, or R⁵ and R⁶ may together form a double    bond    wherein either of R⁴ and R⁶ or R³ and R⁵ may together form a    carbonyl, imine or olefin;    wherein any of two or more of R¹, R², R³, R⁴, R⁵, R⁶ or R⁷, or R^(a)    groups may together form a ring.

The details of one or more embodiments are set forth in the descriptionsbelow. Other features, objects, and advantages will be apparent from thedescription and from the claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 includes a depiction of the virus yield of an RSV inhibitor inaccordance with the invention [RSVP-172944] as a function ofconcentration.

FIG. 2 includes a depiction of the RdRp activity of an RSV inhibitor inaccordance with the invention [RSVP-172944] as a function ofconcentration.

FIG. 3 includes a depiction of the activity of an RSV inhibitor inaccordance with the invention [RSVP-172944] in tabular format.

DETAILED DESCRIPTION

Before the present compounds, compositions, methods and systems aredisclosed and described, it is to be understood that the methods andsystems are not limited to specific synthetic methods, specificcompounds, specific components, or to particular compositions. It isalso to be understood that the terminology used herein is for thepurpose of describing particular embodiments only and is not intended tobe limiting.

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Ranges may be expressed herein as from “about” oneparticular value, and/or to “about” another particular value. When sucha range is expressed, another embodiment includes, from the oneparticular value and/or to the other particular value. Similarly, whenvalues are expressed as approximations, by use of the antecedent“about,” it will be understood that the particular value forms anotherembodiment. It will be further understood that the endpoints of each ofthe ranges are significant both in relation to the other endpoint, andindependently of the other endpoint.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances where itdoes not.

Throughout the description and claims of this specification, the word“comprise” and variations of the word, such as “comprising” and“comprises,” means “including but not limited to,” and is not intendedto exclude, for example, other additives, components, integers or steps.“Exemplary” means “an example of” and is not intended to convey anindication of a preferred or ideal embodiment. “Such as” is not used ina restrictive sense, but for explanatory purposes.

Disclosed are components that can be used to perform the disclosedmethods and systems. These and other components are disclosed herein,and it is understood that when combinations, subsets, interactions,groups, etc. of these components are disclosed that while specificreference of each various individual and collective combinations andpermutation of these may not be explicitly disclosed, each isspecifically contemplated and described herein, for all methods andsystems. This applies to all aspects of this application including, butnot limited to, steps in disclosed methods. Thus, if there are a varietyof additional steps that can be performed it is understood that each ofthese additional steps can be performed with any specific embodiment orcombination of embodiments of the disclosed methods.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer, diastereomer, and meso compound,and a mixture of isomers, such as a racemic or scalemic mixture.

The term “alkyl” as used herein is a branched or unbranched hydrocarbongroup such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, and thelike. The alkyl group can also be substituted or unsubstituted. Unlessstated otherwise, the term “alkyl” contemplates both substituted andunsubstituted alkyl groups. The alkyl group can be substituted with oneor more groups including, but not limited to, alkoxy, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aldehyde, amino,carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl,sulfo-oxo, or thiol as described herein. An alkyl group which containsno double or triple carbon-carbon bonds is designated a saturated alkylgroup, whereas an alkyl group having one or more such bonds isdesignated an unsaturated alkyl group.

Unsaturated alkyl groups having a double bond can be designated alkenylgroups, and unsaturated alkyl groups having a triple bond can bedesignated alkynyl groups. Unless specified to the contrary, the termalkyl embraces both saturated and unsaturated groups.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, etc. The term “heterocycloalkyl” is a cycloalkyl group asdefined above where at least one of the carbon atoms of the ring isreplaced with a heteroatom such as, but not limited to, nitrogen,oxygen, sulfur, selenium or phosphorus. The cycloalkyl group andheterocycloalkyl group can be substituted or unsubstituted. Unlessstated otherwise, the terms “cycloalkyl” and “heterocycloalkyl”contemplate both substituted and unsubstituted cyloalkyl andheterocycloalkyl groups. The cycloalkyl group and heterocycloalkyl groupcan be substituted with one or more groups including, but not limitedto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide,hydroxy, ketone, nitro, silyl, sulfo-oxo, or thiol as described herein.A cycloalkyl group which contains no double or triple carbon-carbonbonds is designated a saturated cycloalkyl group, whereas an cycloalkylgroup having one or more such bonds (yet is still not aromatic) isdesignated an unsaturated cycloalkyl group. Unless specified to thecontrary, the term alkyl embraces both saturated and unsaturated groups.

The term “aryl” as used herein is an aromatic ring composed of carbonatoms. Examples of aryl groups include, but are not limited to, phenyland naphthyl, etc. The term “heteroaryl” is an aryl group as definedabove where at least one of the carbon atoms of the ring is replacedwith a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur,selenium or phosphorus. The aryl group and heteroaryl group can besubstituted or unsubstituted. Unless stated otherwise, the terms “aryl”and “heteroaryl” contemplate both substituted and unsubstituted aryl andheteroaryl groups. The aryl group and heteroaryl group can besubstituted with one or more groups including, but not limited to,alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide,hydroxy, ketone, nitro, silyl, sulfo-oxo, or thiol as described herein.

Exemplary heteroaryl and heterocyclyl rings include: benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aHcarbazolyl, carbolinyl, chromanyl, chromenyL cirrnolinyl,decahydroquinolinyl, 2H,6H˜1,5,2-dithiazinyl, dihydrofuro[2,3b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl,imidazolyl, IH-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl,3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, and xanthenyl.

The terms “alkoxy,” “cycloalkoxy,” “heterocycloalkoxy,” “cycloalkoxy,”“aryloxy,” and “heteroaryloxy” have the aforementioned meanings foralkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, furtherproviding said group is connected via an oxygen atom.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valencies of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc. Unless specifically stated, a substituent that is saidto be “substituted” is meant that the substituent is substituted withone or more of the following: alkyl, alkoxy, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aldehyde, amino,carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl,sulfo-oxo, or thiol as described herein. In a specific example, groupsthat are said to be substituted are substituted with a protic group,which is a group that can be protonated or deprotonated, depending onthe pH.

Unless specified otherwise, the term “patient” refers to any mammalianorganism, including but not limited to, humans.

Pharmaceutically acceptable salts are salts that retain the desiredbiological activity of the parent compound and do not impart undesirabletoxicological effects. Examples of such salts are acid addition saltsformed with inorganic acids, for example, hydrochloric, hydrobromic,sulfuric, phosphoric, and nitric acids and the like; salts formed withorganic acids such as acetic, oxalic, tartaric, succinic, maleic,fumaric, gluconic, citric, malic, methanesulfonic, p-toluenesulfonic,napthalenesulfonic, and polygalacturonic acids, and the like; saltsformed from elemental anions such as chloride, bromide, and iodide;salts formed from metal hydroxides, for example, sodium hydroxide,potassium hydroxide, calcium hydroxide, lithium hydroxide, and magnesiumhydroxide; salts formed from metal carbonates, for example, sodiumcarbonate, potassium carbonate, calcium carbonate, and magnesiumcarbonate; salts formed from metal bicarbonates, for example, sodiumbicarbonate and potassium bicarbonate; salts formed from metal sulfates,for example, sodium sulfate and potassium sulfate; and salts formed frommetal nitrates, for example, sodium nitrate and potassium nitrate.Pharmaceutically acceptable and non-pharmaceutically acceptable saltsmay be prepared using procedures well known in the art, for example, byreacting a sufficiently basic compound such as an amine with a suitableacid comprising a physiologically acceptable anion. Alkali metal (forexample, sodium, potassium, or lithium) or alkaline earth metal (forexample, calcium) salts of carboxylic acids can also be made.

Disclosed herein are compounds, compositions and methods of inhibitingRSV or treating or preventing RSV infection in a patient in need thereofby administering to the patient an effective amount of at least one RSVinhibiting compound. In certain embodiments, the RSV inhibiting compoundhas the structure of Formula I:

or a pharmaceutically acceptable salt thereof, wherein

-   X is selected from O, S, or NR⁷;-   z and y are independently selected from an integer from 0-6;-   R¹ and R² are independently selected from R^(a), OR^(a), N(R^(a))₂,    SR^(a), C(═O)R^(a), C(═O)OR^(a), C(═O)N(R^(a))₂, C(═O)SR^(a),-   wherein R^(a) is in each case independently selected hydrogen, C₁₋₈    alkyl, C₃₋₈ cycloalkyl, C₂₋₈ heterocyclyl, C₆₋₁₂ aryl, C₃₋₁₂    heteroaryl, C₁₋₈ alkyl-C₃₋₈ cycloalkyl, C₁₋₈ alkyl-C₂₋₈    heterocyclyl, C₁₋₈ alkyl-C₆₋₁₂ aryl, and C₁₋₈ alkyl-C₃₋₁₂    heteroaryl; and when N(R^(a))₂ is present, said two R^(a) groups may    together form a ring;-   R³, R⁴, R⁵, and R⁶ are independently selected from independently    selected from —R^(a), —OR^(a), —N(R^(a))₂, —SR^(a), —SO₂R^(a),    —SO₂N(R^(a))₂; —C(O)R^(a), OC(O)R^(a), —COOR^(a), —C(O)N(R^(a))₂,    —OC(O)N(R^(a))₂, —N(R^(a))C(O), —N(R^(a))C(O)N(R^(a))₂, —F, —Cl,    —Br, —I, —CN, —NO₂; wherein R^(a) is independently selected from the    definitions given above,-   R⁷, when present, is R^(a), C(O)R^(a), SO₂R^(a), COOR^(a),    C(O)N(R^(a))₂,    wherein either of R³ and R⁴, or R⁵ and R⁶ may together form a double    bond    wherein either of R⁴ and R⁶ or R³ and R⁵ may together form a    carbonyl, imine or olefin;    wherein any of two or more of R¹, R², R³, R⁴, R⁵, R⁶ or R⁷, or R^(a)    groups may together form a ring.

As used herein, the term olefin includes unsubstituted methylene (e.g.,═CH₂), as well as substituted groups including the functional groupsfalling with the definitions of R³, R⁴, R⁵, or R⁶. The term imineincludes the primary imine (e.g., ═NH) as well as substituted iminesincluding the functional groups falling with the definitions of R⁷.

In certain embodiments, X is S. The RSV inhibiting compound can have thestructure of Formula 1a

wherein R¹-R⁶, y, and z have the meanings given for the compound ofFormula 1.

In some cases, the R³ and R⁴ together form a ring, preferably an aryl orheteroaryl ring. In some instance, the R³ and R⁴ can together form aphenyl ring, e.g., the RSV inhibiting compound can have the structure ofFormula 1 b or 1 b-i:

wherein R¹, R², X, y and z are as defined above, a is selected from 0,1, 2, 3 and 4, and R⁸ includes —R^(a), —OR^(a), —N(R^(a))₂, —SR^(a),—SO₂R^(a), —SO₂N(R^(a))₂; —C(O)R^(a), OC(O)R^(a), —COOR^(a),—C(O)N(R^(a))₂, —OC(O)N(R^(a))₂, —N(R^(a))C(O), —N(R^(a))C(O)N(R^(a))₂,—F, —Cl, —Br, —I, —CN, —NO₂. When multiple R⁸ groups are present, eachR⁸ group is selected independently from the list provided above. In someembodiments, it is preferred that a is 0.

In certain embodiments, it is preferred that z is 0 and y is 1:

wherein R¹-R⁸, X, and a have the meanings given above.

In certain preferred embodiments of the above compounds (e.g., Formula1, Formula 1a, Formula 1b, Formula 1b-I, Formula 1-xy, Formula 1a-xy,Formula 1b-xy, and Formula 1 b-i-xy), R¹ is defined as N(R^(a))₂. Inespecially preferred embodiments, N(R^(a))₂ is a group selected from:

Wherein R⁷ is as defined above, R⁹ is independently selected from—R^(a), —OR^(a), —N(R^(a))₂, —SR^(a), —SO₂R^(a), —SO₂N(R^(a))₂,—C(O)R^(a), OC(O)R^(a), —COOR^(a), —C(O)N(R^(a))₂, —OC(O)N(R^(a))₂,—N(R^(a))C(O), —N(R^(a))C(O)N(R^(a))₂, —F, —Cl, —Br, —I, —CN, —NO₂,wherein R^(a) has the meanings given above, and any two or more R⁹groups may together form a ring, and b is selected from 0, 1, 2, 3 and4. In certain preferred embodiments, R¹ is a group of the formula:

In certain preferred embodiments of the above compounds (e.g., Formula1, Formula 1a, Formula 1b, Formula 1b-I, Formula 1-xy, Formula 1a-xy,Formula 1b-xy, and Formula 1 b-i-xy), R² is defined as C(═O)N(R^(a))₂.For instance, R² can be C(═O)NHR^(a), wherein the R^(a) group present inR² is C₃₋₈ cycloalkyl, C₂₋₈ heterocyclyl, C₆₋₁₂ aryl, or C₃₋₁₂heteroaryl. Preferred groups include C₅₋₆ cycloalkyl and C₆ aryl.

The following compounds in accordance with the present invention andalso known as the “C” series are shown in Table 1 below:

TABLE 1 Compounds of the Invention AVG-044 (172944) C

AVG-045 C

AVG-046 C

AVG-047 C

AVG-048 C

AVG-049 C

AVG-050 C

AVG-051 C

AVG-052 C

AVG-053 C

AVG-054 C

AVG-055 C

AVG-056 C

AVG-057 C

AVG-058 C

AVG-059 C

AVG-060 C

AVG-061 C

AVG-062 C

AVG-063 C

AVG-064 C

AVG-083 C

AVG-084 C

AVG-085 C

AVG-086 C

AVG-087 (purity <90%) C

AVG-111 C

AVG-112 C

AVG-113 C

AVG-114 C

AVG-137 C

AVG-138 C

AVG-139 C

AVG-140 C

AVG-141 C

AVG-142 C

AVG-143 C

AVG-144 C

AVG-145 C

AVG-146 C

AVG-147 C

AVG-148 C

AVG-149 C

AVG-150 C

AVG-151 C

AVG-152 C

AVG-153 C

AVG-154 C

AVG-155 C

AVG-156 C

AVG-182 C

AVG-215 C

AVG-216 C

AVG-217 C

AVG-218 C

AVG-219 C

AVG-220 C

AVG-221 C

AVG-222 C

AVG-223 C

AVG-224 C

AVG-235 C

AVG-236 C

AVG-237 C

AVG-238 C

The compounds defined in the above aspects are RSV antiviral agents andare useful in the treatment of RSV infections. Accordingly, thesecompounds of the invention are useful in the treatment of RSV disease,such as bronchiolitis or pneumonia, or in reducing exacerbation ofunderlying or pre-existing respiratory diseases or conditions whereinRSV infection is a cause of said exacerbation. The underlying orpre-existing respiratory diseases or conditions may include asthma,chronic obstructive pulmonary disease (COPD) and immunosuppression suchas immunosuppression experienced by bone marrow transplant recipients.The compounds above may also be combined with one or more other RSVantiviral agents.

The compounds of the invention may be formulated as pharmaceuticalcompositions and administered to a human patient as set forth in moredetail below. The compounds can be delivered in a number of suitableways including orally, intravenously, topically, parentally,subcutaneously, intradermally, or by inhalation. Exemplary routes ofadministration include buccal, oral, intravenous, intramuscular,topical, subcutaneous, rectal, vaginal, parenteral, pulmonary,intranasal, ophthalmic, and the like, as set forth in more detail below.

Useful dosages of the compounds of the invention for inclusion in thepharmaceutical compositions of the invention can be determined bycomparing in vitro activity and in vivo activity of the compounds inappropriate animal models. Generally, the concentration of thecompound(s) of the invention in a liquid composition will range fromabout 0.1% to about 95% by weight, preferably from about 0.5% to about25% by weight. The concentration in a semi-solid or solid compositionwill range from about 0.1% to 100% by weight, preferably about 0.5% toabout 5% by weight. Single doses for intravenous injection,subcutaneous, intramuscular or topical administration, infusion,ingestion or suppository will generally be from about 0.001 to about5000 mg, and be administered from about 1 to about 3 times daily, toyield levels of about 0.01 to about 500 mg/kg, for adults.

The compounds can be co-administered with one or more other agents forthe treatment or prevention of RSV infection. The other agents can beformulated separately, and administered either at the same or differenttime as the compounds of the instant invention. The other agents can beco-formulated with the compounds of the instant invention to give acombination dosage form.

Pharmaceutical Compositions and Modes of Administration

The invention also provides a pharmaceutical composition comprising acompound of formula (I) and a pharmaceutically acceptable vehicle,excipient or carrier, and the form of this composition can be suitablefor a number of different modes of administration to a patient as setforth below.

The pharmaceutical composition may further comprise or be administeredin combination with one or more other RSV antiviral agents such asVirazole®, BMS-4337715, TMC3531216, MDT-637 (formerly VP-14637),GS-5806, RSV604, ALNRSV01, AL-8176 (or ALS-8176) and/or other agentsthat may be developed as inhibitors of viral entry, assembly,replication, egress or host-virus interactions

The term “composition” is intended to include the formulation of anactive ingredient with conventional vehicles, carriers and excipients,and also with encapsulating materials as the carrier, to give a capsulein which the active ingredient (with or without other carriers) issurrounded by the encapsulation carrier. Any carrier must be“pharmaceutically acceptable” meaning that it is compatible with theother ingredients of the composition and is not deleterious to asubject. The compositions of the present invention may contain othertherapeutic agents as described above, and may be formulated, forexample, by employing conventional solid or liquid vehicles or diluents,as well as pharmaceutical additives of a type appropriate to the mode ofdesired administration (for example, excipients, binders, preservatives,stabilizers, flavours and the like) according to techniques such asthose well known in the art of pharmaceutical formulation (see, forexample, Remington: The Science and Practice of Pharmacy, 21st Ed.,2005, Lippincott Williams & Wilkins).

The pharmaceutical composition includes those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, sub-cutaneous and intravenous) administrationor in a form suitable for administration by inhalation or insufflation.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalcompositions and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, or capsules filled with thesame, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use.

Such pharmaceutical compositions and unit dosage forms thereof maycomprise conventional ingredients in conventional proportions, with orwithout additional active compounds or principles, and such unit dosageforms may contain any suitable effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispensable granules. Asolid carrier can be one or more substances which may also act asdiluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

Suitable vehicles, carriers or excipients include magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter and the like. The term “preparation” isintended to include the formulation of the active compound with anencapsulating material as the carrier by providing a capsule in whichthe active component, with or without carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid forms suitable for oral administration.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

Sterile liquid form compositions include sterile solutions, suspensions,emulsions, syrups and elixirs. The active ingredient can be dissolved orsuspended in a pharmaceutically acceptable carrier, such as sterilewater, sterile organic solvent or a mixture of both.

The compositions according to the present invention may thus beformulated for parenteral administration (for example, by injection, forexample bolus injection or continuous infusion) and may be presented inunit dose form in ampoules, pre-filled syringes, small volume infusionor in multi-dose containers with an added preservative. The compositionsmay take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulation agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilisation from solution, for constitution witha suitable vehicle, for example, sterile, pyrogen-free water, beforeuse.

Pharmaceutical forms suitable for injectable use include sterileinjectable solutions or dispersions, and sterile powders for theextemporaneous preparation of sterile injectable solutions. They shouldbe stable under the conditions of manufacture and storage and may bepreserved against oxidation and the contaminating action ofmicroorganisms such as bacteria or fungi.

The solvent or dispersion medium for the injectable solution ordispersion may contain any of the conventional solvent or carriersystems for the compounds, and may contain, for example, water, ethanol,polyol (for example, glycerol, propylene glycol and liquid polyethyleneglycol and the like), suitable mixtures thereof, and vegetable oils.

Pharmaceutical forms suitable for injectable use may be delivered by anyappropriate route including intravenous, intramuscular, intracerebral,intrathecal, epidural injection or infusion.

Sterile injectable solutions are prepared by incorporating the activecompounds in the required amount in the appropriate solvent with variousother ingredients such as these enumerated above, as required, followedby filtered sterilization. Generally, dispersions are prepared byincorporating the various sterilised active ingredient into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, preferredmethods of preparation are vacuum drying or freeze-drying of apreviously sterile-filtered solution of the active ingredient plus anyadditional desired ingredients.

When the active ingredients are suitably protected they may be orallyadministered, for example, with an inert diluent or with an assimilableedible carrier, or they may be enclosed in hard or soft shell gelatincapsule, or they may be compressed into tablets, or they may beincorporated directly with the food of the diet. For oral therapeuticadministration, the active compound may be incorporated with excipientsand used in the form of ingestible tablets, buccal tablets, troches,capsules, elixirs, suspensions, syrups, wafers and the like.

The amount of active compound in therapeutically useful compositionsshould be sufficient that a suitable dosage will be obtained.

The tablets, troches, pills, capsules and the like may also contain thecomponents as listed hereafter: a binder such as gum, acacia, cornstarch or gelatin; excipients such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; and a sweeteningagent such a sucrose, lactose or saccharin; or a flavouring agent suchas peppermint, oil of wintergreen, or cherry flavouring. When the dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier.

Various other materials may be present as coatings or to otherwisemodify the physical form of the dosage unit. For instance, tablets,pills, or capsules may be coated with shellac, sugar or both. A syrup orelixir may contain the active compound, sucrose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavouring such ascherry or orange flavour. Of course, any material used in preparing anydosage unit form should be pharmaceutically pure and substantiallynon-toxic in the amounts employed. In addition, the active compound(s)may be incorporated into sustained-release preparations andformulations, including those that allow specific delivery of the activepeptide to specific regions of the gut.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,or other well-known suspending agents.

Pharmaceutically acceptable carriers and/or diluents include any and allsolvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilisers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilising agents and thelike.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavoured base, usually sucroseand acacia or tragacanth; pastilles comprising the active ingredient inan inert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multidose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension.

In the case of a spray, this may be achieved for example by means of ametering atomising spray pump. To improve nasal delivery and retentionthe compounds according to the invention may be encapsulated withcyclodextrins, or formulated with other agents expected to enhancedelivery and retention in the nasal mucosa.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, a hydrofluorocarbon (HFC) for examplehydrofluoroalkanes (HFA), carbon dioxide, or other suitable gas.

The aerosol may conveniently also contain a surfactant such as lecithin.The dose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, for example gelatin, or blister packs fromwhich the powder may be administered by means of an inhaler.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 5 to 10 microns or less.Such a particle size may be obtained by means known in the art, forexample by micronization.

When desired, formulations adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

It is especially advantageous to formulate parenteral compositions indosage unit form for ease of administration and uniformity of dosage.Dosage unit form as used herein refers to physically discrete unitssuited as unitary dosages for the subjects to be treated; each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect in association with the requiredpharmaceutical carrier. The specification for the novel dosage unitforms of the invention are dictated by and directly dependent on (a) theunique characteristics of the active material and the particulartherapeutic effect to be achieved, and (b) the limitations inherent inthe art of compounding such an active material for the treatment ofviral infection in living subjects having a diseased condition in whichbodily health is impaired as herein disclosed in detail.

The invention also includes the compounds in the absence of carrierwhere the compounds are in unit dosage form.

Liquids or powders for intranasal administration, tablets or capsulesfor oral administration and liquids for intravenous administration arethe preferred compositions.

The compounds as set forth above can be useful in a method of inhibitingRSV or in treating or preventing an RSV infection of other infectionscaused by related members of the paramyxovirus family such as mumpsvirus, human parainfluenzaviruses, and Nipah and hendra virus. Thereference to RSV as used hereinbelow also include these related membersor the paramyxovirus family compounds can also be used to treat an RSVdisease or reduce exacerbation of an underlying or pre-existingrespiratory disease wherein RSV infection is a cause of saidexacerbation. The RSV disease may include bronchiolitis or pneumonia.The underlying or pre-existing respiratory diseases or conditions mayinclude asthma, chronic obstructive pulmonary disease (COPD) andimmunosuppression such as immunosuppression experienced by bone marrowtransplant recipients.

Treatment may be therapeutic treatment or prophylactic treatment orprevention. Generally, the term “treating” means affecting a subject,tissue or cell to obtain a desired pharmacological and/or physiologicaleffect and includes: (a) inhibiting the viral infection or RSV disease,such as by arresting its development or further development; (b)relieving or ameliorating the effects of the viral infection or RSVdisease, such as by causing regression of the effects of the viralinfection or RSV disease; (c) reducing the incidence of the viralinfection or RSV disease or (d) preventing the viral infection or RSVdisease from occurring in a subject, tissue or cell predisposed to theviral infection or RSV disease or at risk thereof, but has not yet beendiagnosed with a protective pharmacological and/or physiological effectso that the viral infection or RSV disease does not develop or occur inthe subject, tissue or cell.

The term “subject” refers to any animal, in particular mammals such ashumans, having a disease which requires treatment with the compound offormula (I). Particularly preferred treatment groups include at riskpopulations such as hospitalised subjects, the elderly, high-risk adultsand infants. In one embodiment of the invention, an effective amount ofthe above compounds, or pharmaceutical compositions thereof, isadministered to a patient or subject in need thereof.

The term “administering” or “administered” should be understood to meanproviding a compound or pharmaceutical composition of the invention to asubject suffering from or at risk of the disease or condition to betreated or prevented.

As indicated above, although the invention has been described withparticular reference to treating RSV infections and diseases, moreparticularly human and animal RSV infections or diseases, it will beappreciated that the invention may also be useful in the treatment ofother viruses of the sub-family Pneumovirinae, more particularly, thegenera Pneumovirus and Metapneumovirus.

Dosages

The term “therapeutically effective amount” refers to the amount of thecompound of formula (I) that will elicit the biological or medicalresponse of a subject, tissue or cell that is being sought by theresearcher, veterinarian, medical doctor or other clinician.

By “effective amount” is generally considered that amount that will beeffective to treat the condition sought to be treated, or to inhibitRSV, and this effective amount is variable based on a variety of factorsincluding age, size and condition of the patient being treated.Accordingly, one skilled in the art would be readily able to determinethe specific effective amount for each patient being treated for RSV, anRSV-related condition, or to inhibit RSV in a given case.

In the treatment of RSV infections or diseases, an appropriate dosagelevel will generally be about 0.01 to about 500 mg per kg subject bodyweight per day which can be administered in single or multiple doses.The dosage may be selected, for example, to any dose within any of theseranges, for therapeutic efficacy and/or symptomatic adjustment of thedosage to the subject to be treated.

As indicated above, it will be understood that the specific dose leveland frequency of dosage for any particular subject may be varied andwill depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular condition, and the subject undergoingtherapy.

Methods of Preparation

The compounds of the invention may generally be prepared by thefollowing methods. Unless otherwise stated, the groups of each of thecompounds are as previously defined.

General information regarding method of preparation: In the syntheses ofthe present invention, all evaporations were carried out in vacuo with arotary evaporator. Analytical samples were dried in vacuo (1-5 mmHg) atrt. Thin layer chromatography (TLC) was performed on silica gel plates,spots were visualized by UV light (214 and 254 nm). Purification bycolumn and flash chromatography was carried out using silica gel(200-300 mesh). Solvent systems are reported as mixtures by volume. AllNMR spectra were recorded on a Bruker 400 (400 MHz) spectrometer. 1Hchemical shifts are reported in 5 values in ppm with the deuteratedsolvent as the internal standard. Data are reported as follows: chemicalshift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet,br=broad, m=multiplet), coupling constant (Hz), integration.

As described further below, the general method for producing compoundsin accordance with the invention is shown schematically as follows:

Additional information regarding this general method is included in theExamples below.

Examples

The following examples are set forth below to illustrate the methods andresults according to the disclosed subject matter. These examples arenot intended to be inclusive of all aspects of the subject matterdisclosed herein, but rather to illustrate representative methods,compositions, and results. These examples are not intended to excludeequivalents and variations of the present invention, which are apparentto one skilled in the art.

Efforts have been made to ensure accuracy with respect to numbers (e.g.,amounts, temperature, etc.) but some errors and deviations should beaccounted for. Unless indicated otherwise, parts are parts by weight,temperature is in ° C. or is at ambient temperature, and pressure is ator near atmospheric. There are numerous variations and combinations ofreaction conditions, e.g., component concentrations, temperatures,pressures, and other reaction ranges and conditions that can be used tooptimize the product purity and yield obtained from the describedprocess. Only reasonable and routine experimentation will be required tooptimize such process conditions.

Example 1

General Method of Preparation of the Compounds of the Invention

In all of the experimental data as reported below, the followingabbreviations are used:

rt: room temperature

UV: ultra violet

HPLC: high pressure liquid chromatography

Rt: retention time

LCMS: Liquid chromatography mass spectroscopy

NMR: Nuclear magnetic resonance spectroscopy

CC: column chromatography

TLC: thin layer chromatography

sat: saturated

aq: aqueous

DCM: dichloromethane

DCE: dichloroethane

DMF: dimethylformamide

DIPEA: diisopropylethylamine

EtOAc: ethyl acetate

TEA: triethylamine

THF: tetrahydrofurane

TFA: trifluoroacetic acid

t-BuOK: Potassium tert-butoxide

n-BuOH: n-Butanol

EtOH: Ethanol

HOAc: acetic acid

o/n: overnight

h: hour(s)

min: minutes

HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

LiHMDS: Lithium bis(trimethylsilyl)amide

General information: All evaporations were carried out in vacuo with arotary evaporator. Analytical samples were dried in vacuo (1-5 mmHg) atrt. Thin layer chromatography (TLC) was performed on silica gel plates,spots were visualized by UV light (214 and 254 nm). Purification bycolumn and flash chromatography was carried out using silica gel(200-300 mesh). Solvent systems are reported as mixtures by volume. AllNMR spectra were recorded on a Bruker 400 (400 MHz) spectrometer. 1Hchemical shifts are reported in 5 values in ppm with the deuteratedsolvent as the internal standard. Data are reported as follows: chemicalshift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet,br=broad, m=multiplet), coupling constant (Hz), integration.

General Synthetic Method

The general synthetic method for producing the compounds of theinvention is set forth below:

Exemplary Experimental Procedures for the General Method

1. The synthesis of 2H-benzo[b][1,4]thiazin-3(4H)-one (C-2) is shown asfollows:

A mixture of C-1 (20.0 g, 159.8 mmol), methyl 2-chloroacetate (20.8 g,191.7 mmol) and KOH (17.9 g, 319.5 mmol) in water (80 mL) and EtOH (400mL) was stirred at 80° C. for 20 h. The mixture was concentrated invacuo. The residue was diluted with water (150 mL) and stirred forseveral minutes. The resulting solid was collected by filtration, washedwith water (100 mL×3) and dried in vacuo to get the desired compound C-2(14.5 g, 55% yield) as a light brown solid.

Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5μm); Column Temperature: 40° C.; Flow Rate: 1.5 mL/min; Mobile Phase:from 95% [water+0.05% TFA] and 5% [CH₃CN+0.05% TFA] to 0% [water+0.05%TFA] and 100% [CH₃CN+0.05% TFA] in 1.5 min, then under this conditionfor 0.5 min, finally changed to 95% [water+0.05% TFA] and 5%[CH₃CN+0.05% TFA] in 0.1 min and under this condition for 0.1 min.Purity is 98.7% (in 254 nm). Rt=0.870 min; MS Calcd.: 165.1; MS Found:166.3 [M+H]⁺.

2. The synthesis of tert-butyl2-(3-oxo-2H-benzo[b][1,4]thiazin-4(3H)-yl)acetate (C-3) is shown asfollows:

To a solution of C-2 (20.0 g, 121.1 mmol) in DMF (150 mL) was added NaH(60%, 5.3 g, 133.2 mmol) in portions and the temperature was maintainedat 0° C. After being stirred for 10 min, tert-butyl 2-bromoacetate (28.3g, 145.3 mmol) was added dropwise over 5 min. After the addition, thereaction mixture was stirred at room temperature for 2 h. The mixturewas diluted with water (200 mL) and extracted with ethyl acetate (100mL×3). The combined organic layers were washed with brine (100 mL×2),dried over sodium sulfate, and concentrated to dryness. The residue waspurified by column chromatography on silica gel (petrol ether/EtOAc=5/1)to give C-3 (18.0 g, 53% yield) as yellow oil.

Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; Mobile Phase:from 95% [water+0.05% TFA] and 5% [CH₃CN+0.05% TFA] to 0% [water+0.05%TFA] and 100% [CH₃CN+0.05% TFA] in 1.6 min, then under this conditionfor 1.4 min, finally changed to 95% [water+0.05% TFA] and 5%[CH₃CN+0.05% TFA] in 0.05 min and under this condition for 0.7 min.Rt=1.874 min; MS Calcd.: 279.1; MS Found: 302.2 [M+Na]⁺.

3. The synthesis of ethyl4-(2-tert-butoxy-2-oxoethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-2-carboxylate(C-4d) is shown as follows:

To a solution of C-3 (10.0 g, 35.8 mmol) in THF (150 mL) at −78° C. wasadded LiHMDS (1 M in THF, 71.6 mL, 71.6 mmol) dropwise. After beingstirred for 10 min at this temperature, ethyl carbonochloridate (3.9 g,35.8 mmol) was added dropwise over 5 min and the reaction mixture wasstirred at −78° C. for 2 h. The mixture was diluted with sat. NH₄Clsolution (100 mL) and extracted with ethyl acetate (80 mL×3). Thecombined organic layers were washed with brine (100 mL×2), dried oversodium sulfate, and concentrated to dryness. The residue was purified bycolumn chromatography on silica gel (petrol ether/EtOAc=4/1) to giveC-4d (8.0 g, 64% yield) as brown oil.

Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; Mobile Phase:from 95% [water+0.05% TFA] and 5% [CH₃CN+0.05% TFA] to 0% [water+0.05%TFA] and 100% [CH₃CN+0.05% TFA] in 1.6 min, then under this conditionfor 1.4 min, finally changed to 95% [water+0.05% TFA] and 5%[CH₃CN+0.05% TFA] in 0.05 min and under this condition for 0.7 min.Purity is 74.7%. Rt=1.923 min; MS Calcd.: 351.1; MS Found: 374.0[M+Na]⁺.

4. The synthesis of2-(2-(ethoxycarbonyl)-3-oxo-2H-benzo[b][1,4]thiazin-4(3H)-yl)acetic acid(C-5f) is shown as follows:

A mixture of C-4d (150 mg, 0.43 mmol) in TFA (2 mL) was stirred at roomtemperature for 1 h. The solvent was removed by concentration to giveC-5f (120 mg, 95% yield) as yellow oil, which was used for next stepdirectly.

Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; Mobile Phase:from 95% [water+0.05% TFA] and 5% [CH₃CN+0.05% TFA] to 0% [water+0.05%TFA] and 100% [CH₃CN+0.05% TFA] in 1.6 min, then under this conditionfor 1.4 min, finally changed to 95% [water+0.05% TFA] and 5%[CH₃CN+0.05% TFA] in 0.05 min and under this condition for 0.7 min.Purity is 72.1%. Rt=1.526 min; MS Calcd.: 295.0; MS Found: 296.0 [M+H]⁺.

5. The synthesis of ethyl4-(2-(cyclohexylamino)-2-oxoethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-2-carboxylate(C-6f) is shown as follows:

A mixture of C-5f (120 mg, 0.41 mmol), HATU (311 mg, 0.82 mmol), DIPEA(210 mg, 1.63 mmol) and cyclohexanamine (40 mg, 0.41 mmol) in THF (5 mL)was stirred at room temperature under nitrogen for 16 h. The mixture wasdiluted with water (30 mL) and extracted with ethyl acetate (20 mL×3).The combined organic layers were washed with brine (20 mL×2), dried oversodium sulfate, and concentrated to dryness. The residue was purified bycolumn chromatography on silica gel (petrol ether/EtOAc=2/1) to giveC-6f (110 mg, 72% yield) as brown oil.

Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5um); Column Temperature: 40° C.; Flow Rate: 1.5 mL/min; Mobile Phase:from 95% [water+0.05% TFA] and 5% [CH₃CN+0.05% TFA] to 0% [water+0.05%TFA] and 100% [CH₃CN+0.05% TFA] in 1.5 min, then under this conditionfor 0.5 min, finally changed to 95% [water+0.05% TFA] and 5%[CH₃CN+0.05% TFA] in 0.1 min and under this condition for 0.1 min.Purity is >95% (in 254 nm). Rt=1.280 min; MS Calcd.: 376.1; MS Found:377.4 [M+H]⁺.

6. The synthesis of4-(2-(cyclohexylamino)-2-oxoethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-2-carboxylicacid (C-7f) is shown as follows:

To a solution of C-6f (100 mg, 0.27 mmol) in MeOH (6 mL) was added 2 NNaOH (0.27 mL, 0.54 mmol). The reaction mixture was stirred at roomtemperature for 1 h. The mixture was diluted with water (20 mL), thenadjusted to pH=2-3 with diluted hydrochloric acid and extracted withethyl acetate (20 mL×3). The combined organic layers were washed withbrine (20 mL×2), dried over sodium sulfate, and concentrated to drynessto give C-7f (90 mg, 97% yield) as a white solid.

Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5um); Column Temperature: 40° C.; Flow Rate: 1.5 mL/min; Mobile Phase:from 95% [water+0.05% TFA] and 5% [CH₃CN+0.05% TFA] to 0% [water+0.05%TFA] and 100% [CH₃CN+0.05% TFA] in 1.5 min, then under this conditionfor 0.5 min, finally changed to 95% [water+0.05% TFA] and 5%[CH₃CN+0.05% TFA] in 0.1 min and under this condition for 0.1 min.Purity is >99% (in 254 nm). Rt=1.096 min; MS Calcd.: 348.1; MS Found:349.3 [M+H]⁺.

7. The synthesis ofN-cyclohexyl-2-(3-oxo-2-(piperidine-1-carbonyl)-2H-benzo[b][1,4]thiazin-4(3H)-yl)acetamide (AVG-044) is shown as follows:

A mixture of C-7f (90 mg, 0.26 mmol), HATU (160 mg, 0.42 mmol), DIPEA(134 mg, 1.03 mmol) and piperidine (22 mg, 0.26 mmol) in THF (4 mL) wasstirred at room temperature under nitrogen for 16 h. The mixture wasdiluted with water (20 mL) and extracted with ethyl acetate (20 mL×3).The combined organic layers were washed with brine (20 mL×2), dried oversodium sulfate, and concentrated to dryness. The residue was purified byPrep-TLC (petrol ether/EtOAc=1/1) to give AVG-044 (23 mg, 21% yield) asa white solid.

Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; Mobile Phase:from 95% [water+0.05% TFA] and 5% [CH₃CN+0.05% TFA] to 0% [water+0.05%TFA] and 100% [CH₃CN+0.05% TFA] in 3.0 min, then under this conditionfor 1.0 min, finally changed to 95% [water+0.05% TFA] and 5%[CH₃CN+0.05% TFA] in 0.05 min and under this condition for 0.7 min.Purity is 97.3%. Rt=2.684 min; MS Calcd.: 415.2; MS Found: 416.1 [M+H]⁺.

Agilent HPLC 1200; Column: L-column2 ODS (150 mm*4.6 mm*5.0 μm); ColumnTemperature: 40° C.; Flow Rate: 1.0 mL/min; Mobile Phase: from 95%[water+0.1% TFA] and 5% [CH₃CN+0.1% TFA] to 0% [water+0.1% TFA] and 100%[CH₃CN+0.1% TFA] in 10 min, then under this condition for 5 min, finallychanged to 95% [water+0.1% TFA] and 5% [CH₃CN+0.1% TFA] in 0.1 min andunder this condition for 5 min. Purity is 97.3%. Rt=9.907 min.

¹H NMR (400 MHz, CDCl₃) δ 8.03 (d, J=7.6 Hz, 1H), 7.33 (dd, J=7.8, 1.4Hz, 1H), 7.26-7.24 (m, 1H), 7.06 (ddd, J=7.6, 7.6, 0.8 Hz, 1H), 6.94(dd, J=8.4, 0.8 Hz, 1H), 5.39 (d, J=17.2 Hz, 1H), 4.41 (s, 1H), 3.86 (d,J=17.2 Hz, 1H), 3.83-3.76 (m, 1H), 3.57-3.51 (m, 2H), 3.41-3.16 (m, 2H),1.84-1.81 (m, 2H), 1.69-1.65 (m, 6H), 1.58-1.55 (m, 2H), 1.43-1.35 (m,1H), 1.33-1.25 (m, 2H), 1.20-1.03 (m, 3H).

7. The synthesis ofN-cyclohexyl-2-(2-(morpholine-4-carbonyl)-3-oxo-2H-benzo[b][1,4]thiazin-4(3H)-yl)acetamide (AVG-054) is shown as follows:

A mixture of C-7f (90 mg, 0.26 mmol), HATU (160 mg, 0.42 mmol), DIPEA(134 mg, 1.03 mmol) and morpholine (23 mg, 0.26 mmol) in THF (4 mL) wasstirred at room temperature under nitrogen for 16 h. The mixture wasdiluted with water (20 mL) and extracted with ethyl acetate (20 mL×3).The combined organic layers were washed with brine (20 mL×2), dried oversodium sulfate, and concentrated to dryness. The residue was purified byPrep-HPLC to give AVG-054 (24 mg, 22% yield) as a white solid.

Prep-HPLC Condition:

1.1 Chromatographic Equipment

-   -   Gilson Prep-HPLC system: GX-281 sample manager, 306 pump, 806        Manometric module, 811 D DYNAMIC Mixer, UVNIS-156

1.2 Chromatographic Condition

-   -   Column: Waters X-Bridge™ Prep C18 5 μm OBD™, 30×100 mm    -   Flowrate: 20 mL/min    -   Gradient:

Water (0.04% Time(min) MeOH NH₄HCO₃)  0 55 45  8.0 80 20  9 95  5 13.595  5 13.6 55 45 17.6 55 45

Wavelength: 214 nm and 254 nm.

Agilent LCMS 1200-6110, Column: Waters X-Bridge C18 (50 mm*4.6 mm*3.5μm); Column Temperature: 40° C.; Flow Rate: 2.0 mL/min; Mobile Phase:from 95% [water+0.05% TFA] and 5% [CH₃CN+0.05% TFA] to 0% [water+0.05%TFA] and 100% [CH₃CN+0.05% TFA] in 3.0 min, then under this conditionfor 1.0 min, finally changed to 95% [water+0.05% TFA] and 5%[CH₃CN+0.05% TFA] in 0.05 min and under this condition for 0.7 min.Purity is >99%. Rt=2.268 min; MS Calcd.: 417.2; MS Found: 418.0 [M+H]⁺.

Agilent HPLC 1200; Column: L-column2 ODS (150 mm*4.6 mm*5.0 μm); ColumnTemperature: 40° C.; Flow Rate: 1.0 mL/min; Mobile Phase: from 95%[water+0.1% TFA] and 5% [CH₃CN+0.1% TFA] to 0% [water+0.1% TFA] and 100%[CH₃CN+0.1% TFA] in 10 min, then under this condition for 5 min, finallychanged to 95% [water+0.1% TFA] and 5% [CH₃CN+0.1% TFA] in 0.1 min andunder this condition for 5 min. Purity is >99%. Rt=8.103 min.

¹H NMR (400 MHz, CDCl₃) δ 7.86 (d, J=8.0 Hz, 1H), 7.34 (dd, J=7.6, 1.2Hz, 1H), 7.31-7.27 (m, 1H), 7.08 (ddd, J=7.6, 7.4, 0.8 Hz, 1H), 6.96(dd, J=8.2, 1.0 Hz, 1H), 5.39 (d, J=17.2 Hz, 1H), 4.39 (s, 1H), 3.90 (d,J=17.2 Hz, 1H), 3.84-3.74 (m, 3H), 3.71-3.62 (m, 2H), 3.59-3.49 (m, 2H),3.47-3.37 (m, 2H), 1.85-1.81 (m, 2H), 1.72-1.60 (m, 2H), 1.48-1.22 (m,3H), 1.19-1.01 (m, 3H).

Example 2

Cell Lines and Transfections

Human carcinoma (HEp-2, ATCC CCL-23), human lung carcinoma (A549, ATCCCCL-185), human bronchial epithelial (BEAS-2B, ATCC CRL-9609), humanembryonic kidney (293T, ATCC CRL-3216), and Madin Darby canine kidney(MDCK, ATCC CCL-34) cells were maintained at 37° C. and 5% CO2 inDulbecco's modified Eagle's medium (DMEM) supplemented with 7.5% fetalbovine serum. Lipofectamine 2000 or GeneJuice were used for alltransient transfection reactions.

RSV Amplification and Virion Purification

recRSV stocks were grown on HEp-2 cells inoculated at a multiplicity ofinfection (MOI) of 0.01 pfu/cell. Infected cells were kept for 16 hoursat 37° C., followed by incubation at 32° C. for five to seven days.Cell-associated progeny virus was released through one freeze/thaw cycleand titers determined by TCID₅₀ titration on HEp-2 cells. Twoalternative strategies were explored to remove contaminating luciferaseproteins from virus stocks. Progeny virions in culture supernatants (IAVstocks) or released through one freeze/thaw cycle from infected cells(RSV stocks) were cleared (4,000×g for 20 minutes at 4° C.), thenpelleted (60,000×g for 30 minutes at 4° C.). Pelleted material wasresuspended in TNE buffer (50 mM Tris/Cl pH 7.2, 10 mM EDTA) andpurified through a 20/60% one-step sucrose gradient in TNE buffer(100,000×g for 90 minutes at 4° C.). Virions were harvested from thegradient intersection.

Automated HTS Protocol in 384-Well Plate Format

BEAS-2B cells (8×10³/well) were injected in 30 μl/well into barcodedwhite wall/clear bottom 384-well plates using a MultiFlo automateddispenser (BioTek) equipped with dual 10-μl peristaltic pump manifolds,collected (150×g for 90 seconds at 25° C.), and incubated for five hoursat 37° C. and 5% CO₂. Compound was added to a final concentration of 5μM (20 nl/well) using a high-density pin tool (V&P Scientific) attachedto the pipetting head of Hamilton Nimbus liquid handler, followed byinfection in 10 μl/well using the MultiFlo dispenser unit, spincollection (150×g for 90 seconds at 25° C.), and incubation for 40 hoursat 37° C. and 5% CO₂. Final vehicle (DMSO) concentration was 0.05%.Barcodes of source and assay plates were automatically detected andrecorded by the Nimbus unit at the time of stamping. Using a stackerunit with integrated barcode reader (Biotek) attached to an H1 Bioteksynergy plate reader, plates were automatically loaded, luciferasesubstrates (15 μl/well) injected, and bioluminescence recorded after athree minute lag time. Readouts were automatically saved by platebarcode. For analysis of primary screen raw data, normalized relativeinhibition values were calculated for each compound by subtracting eachvalue from the average of the plate vehicle controls, followed bydividing the results by the difference between the means of platevehicle and positive controls. Hits candidates were defined as compoundsshowing ≥75% inhibition of normalized signal intensity against either orboth viral targets.

Dose-Response Counterscreens

Two-fold serial dilutions of hit candidates were prepared in 384-wellplates in three replicates each using the Nimbus liquid handler. BEAS-2Bcells (8×10³/well) were then plated as before, serial dilutionstransferred using the pin-tool, and cells infected with recombinantvirus strains expressing distinct luciferase reporter proteins or leftuninfected for cell viability assessment. Reporter signals were recordedas outlined above. To determine cell viability, PrestoBlue substrate(life technologies) was added after 40-hour incubation of cells at 37°C. (5 μl/well) and top-read fluorescence (excitation 560 nm; emission590 nm; instrument gain 85) recorded after 45 minutes of incubation at37° C. using the H1 synergy plate reader. Four-parameter variable sloperegression modeling was applied to determine 50% active (EC₅₀) and toxic(CC₅₀) concentrations.

RSV Minigenome Reporter Assays

An RSV minigenome reporter plasmid (pHH-RSV-repl-firefly) wasconstructed under the control of the constitutive RNA pol I promoter bygenerating a firefly luciferase open reading frame flanked by the 5′-and 3′-non-coding regions and transfer into a pHH plasmid backboneharboring an RNA pol I promoter. Huh-7 cells were co-transfected withthis plasmid and expression plasmids pRSV-L, pRSV-M2-1, pRSV-N andpRSV-P, which encode the RSV polymerase protein subunits. Test compoundswere added in serial dilutions, luciferase reporter activitiesdetermined 40 hours post-transfection, and EC₅₀ concentrationscalculated if possible.

Virus Yield Reduction Assay

Hep2 cells were seeded in a 12-well plate format and exposed to serialdilutions of compound (3-fold, 20 μM highest), followed by infectionwith recombinant RSV-A2 harboring the fusion protein of the L19F isolateat a multiplicity of infection (MOI) of 0.1. Cell-associated progenyvirions were harvested after 48-hour incubation at 37° C. and subjectedto TCID₅₀ titration on Hep2 cells. Viral titers were calculated based onthe Spearman Karber method and inhibitory concentrations based on virusyields determined through four-parameter variable slope regressionmodeling.

Statistical Analysis

The Excel and Prism 6 (GraphPad) software packages were used for dataanalysis. Statistical significance of differences between sample groupswere assessed by unpaired two-tailed t tests or one-way analysis ofvariance (ANOVA) in combination with Tukey's multiple comparisonpost-tests, respectively.

Assay results for RSV-172944 are presented in FIGS. 1-2.

The compositions and methods of the appended claims are not limited inscope by the specific compositions and methods described herein, whichare intended as illustrations of a few aspects of the claims and anycompositions and methods that are functionally equivalent are intendedto fall within the scope of the claims. Various modifications of thecompositions and methods in addition to those shown and described hereinare intended to fall within the scope of the appended claims. Further,while only certain representative compositions and method stepsdisclosed herein are specifically described, other combinations of thecompositions and method steps also are intended to fall within the scopeof the appended claims, even if not specifically recited. Thus, acombination of steps, elements, components, or constituents may beexplicitly mentioned herein or less, however, other combinations ofsteps, elements, components, and constituents are included, even thoughnot explicitly stated. The term “comprising” and variations thereof asused herein is used synonymously with the term “including” andvariations thereof and are open, non-limiting terms. Although the terms“comprising” and “including” have been used herein to describe variousembodiments, the terms “consisting essentially of” and “consisting of”can be used in place of “comprising” and “including” to provide for morespecific embodiments of the invention and are also disclosed. Other thanin the examples, or where otherwise noted, all numbers expressingquantities of ingredients, reaction conditions, and so forth used in thespecification and claims are to be understood at the very least, and notas an attempt to limit the application of the doctrine of equivalents tothe scope of the claims, to be construed in light of the number ofsignificant digits and ordinary rounding approaches.

Example 3: Additional Testing of the C Series Compounds

Additional testing was conducted to determine additional parameters ofthe compounds of the invention. In the following Table, a group ofselected C series compounds was analyzed with regard to MS, LC, and NMR,and the results are provided below.

Compound Rt(min) Rt(Min) ID Structure M + 1 (LCMS) (HPLC) Method 1HNMR(400 MHz) AVG-044

416.1 2.68 9.91 C (CDCl₃) δ 8.03 (d, J = 7.6 Hz, 1H), 7.33 (dd, J = 7.8,1.4 Hz, 1H), 7.26- 7.24 (m, 1H), 7.06 (ddd, J = 7.6, 7.6, 0.8 Hz, 1H),6.94 (dd, J = 8.4, 0.8 Hz, 1H), 5.39 (d, J = 17.2 Hz, 1H), 4.41 (s, 1H),3.86 (d, J = 17.2 Hz, 1H), 3.83-3.76 (m, 1H), 3.57-3.51 (m, 2H),3.41-3.16 (m, 2H), 1.84- 1.81 (m, 2H), 1.69-1.65 (m, 6H), 1.58-1.55 (m,2H), 1.43-1.35 (m, 1H), 1.33-1.25 (m, 2H), 1.20- 1.03 (m, 3H). AVG-045

418.3 2.23 8.00 C (CDCl₃) δ 8.32 (d, J = 7.2 Hz, 1H), 7.34 (d, J = 7.6Hz, 1H), 7.29-7.28 (m, 1H), 7.08 (dd, J = 7.6, 7.2 Hz, 1H), 6.92 (d, J =8.4 Hz, 1H), 5.43 (d, J = 17.2 Hz, 1H), 4.42 (s, 1H), 4.06-4.04 (m, 1H),3.92-3.88 (m, 3H), 3.57-3.54 (m, 2H), 3.47-3.42 (m, 2H), 3.37- 3.35 (m,1H), 3.26-3.25 (m, 1H), 1.78-1.71 (m, 3H), 1.69-1.64 (m, 3H), 1.52-1.48(m, 2H), 1.40- 1.38 (m, 2H) AVG-046

417.3 1.84 6.43 C (CDCl₃) δ 8.25 (d, J = 7.6 Hz, 1H), 7.34 (dd, J = 7.8,1.4 Hz, 1H), 7.29- 7.24 (m, 1H), 7.06 (ddd, J = 7.8, 7.4, 1.2 Hz, 1H),6.92 (dd, J = 8.4, 0.8 Hz, 1H), 5.41 (d, J = 17.2 Hz, 1H), 4.41 (s, 1H),4.0-3.90 (m, 1H), 3.90 (d, J = 17.2 Hz, 1H), 3.60-3.53 (m, 2H),3.38-3.30 (m, 1H), 3.26- 3.19 (m, 1H), 3.10-3.02 (m, 2H), 2.73-2.65 (m,2H), 1.86-1.85 (m, 2H), 1.77-1.60 (m, 4H), 1.53- 1.50 (m, 2H), 1.45-1.35(m, 3H). AVG-047

431.3 1.97 7.07 C (CDCl₃) δ 8.27 (d, J = 6.8 Hz, 1H), 7.34 (dd, J = 8.0,1.2 Hz, 1H), 7.28- 7.24 (m, 1H), 7.6 (ddd, J = 7.8, 7.4, 1.2 Hz, 1H),6.91 (dd, J = 8.4, 0.8 Hz, 1H), 5.42 (d, J = 17.6 Hz, 1H), 4.40 (s, 1H),3.92-3.86 (m, 2H), 3.58-3.53 (m, 2H), 3.34- 3.33 (m, 1H), 3.26-3.21 (m,1H), 2.86-2.83 (m, 2H), 2.31 (s, 3H), 2.18- 2.15 (m, 2H), 1.86-1.84 (m,2H), 1.77-1.70 (m, 3H), 1.54-1.50 (m, 4H), 1.40-1.32 (m, 1H) AVG-048

376.2 2.47 8.83 C (CDCl₃) δ 8.10 (d, J = 6.8 Hz, 1H), δ 7.33 (dd, J =7.8, 1.4 Hz, 1H), 7.26-7.24 (m, 1H), 7.06 (ddd, J = 7.6, 7.2, 1.2 Hz,1H), 6.93 (dd, J = 8.4, 0.8 Hz, 1H), 5.38 (d, J = 17.2 Hz, 1H), 4.41 (s,1H), 4.12-4.10 (m, 1H), 3.88 (d, J = 17.2 Hz, 1H), 3.57-3.53 (m, 2H),3.29-3.21 (m, 2H), 1.70-1.64 (m, 4H), 1.53-1.39 (m, 1H), 1.11- 1.09 (m,1H), 1.10 (dd, J = 6.4, 0.8 Hz, 6H). AVG-049

430.3 2.89, 2.91 10.28, 10.36 C (CDCl₃) δ 8.04-7.96 (m, 1H), 7.37-7.30(m, 1H), 7.29-7.25 (m, 1H), 7.08- 7.05 (m, 1H), 6.98-6.96 (m, 1H),5.41-5.36 (m, 1H), 4.43-4.41 (m, 1H), 4.06-3.73 (m, 2H), 3.61- 3.44 (m,2H), 3.42-3.18 (m, 2H), 1.89-1.75 (m, 1H), 1.69-1.64 (m, 4H), 1.54-1.50(m,4H), 1.48- 1.32 (m, 3H), 1.32-1.22 (m, 2H), 1.26-1.14 (m, 1H),1.09-0.88 (m, 1H), 0.88-0.84 (m, 1H), 0.83- 0.78 (m, 2H). AVG-050

444.3 2.99 10.62 C (CDCl₃) δ 8.10 (d, J = 8.4 Hz, 1H), 7.33 (dd, J =7.8, 1.4 Hz, 1H), 7.26- 7.21 (m, 1H), 7.06 (dd, J = 7.6, 7.6, 1.2 Hz,1H), 6.95 (dd, J = 8.2, 1.0 Hz, 1H), 5.39 (d, J = 17.6 Hz, 1H), 4.42 (s,1H), 3.89 (d, J = 17.2 Hz, 1H), 3.77 (m, 1H), 3.55 (m, 2H), 3.39-3.30(m, 1H), 3.30-3.18 (m, 1H), 1.69-1.67 (m, 3H), 1.66-1.65 (m, 3H), 1.53-1.46 (m, 1H), 1.45-1.36 (m, 2H), 1.36-1.32 (m 3H), 1.29-1.25 (m, 1H),1.26-1.24 (m, 1H) , 0.87 (s, 3H), 0.82 (s, 3H). AVG-051

402.3 2.6 9.25 C (CDCl₃) δ 8.16 (d, J = 6.8 Hz, 1H), 7.33 (dd, J = 7.6,1.6 Hz, 1H), 7.26- 7.20 (m, 1H), 7.06 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H),6.93 (dd, J = 8.2, 0.6 Hz, 1H), 5.40 (d, J = 17.2 Hz, 1H), 4.41 (s, 1H),4.26-4.25 (m, 1H), 3.88 (d, J = 17.2 Hz, 1H), 3.59-3.46 (m, 2H),3.37-3.34 (m, 1H), 3.26- 3.24 (m, 1H), 1.87 (m, 2H), 1.77-1.59 (m, 5H),1.55-1.44 (m, 5H), 1.44- 1.24 (m, 2H). AVG-052

424.2 2.71 9.66 C (CDCl₃) δ 9.58 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.36(dd, J = 7.6, 1.6 Hz, 1H), 7.35-7.26 (m, 1H), 7.20-7.12 (m, 3H),7.13-7.07 (m, 2H), 5.63 (d, J = 17.2 Hz, 1H), 4.47 (s, 1H), 4.09 (d, J =17.6 Hz, 1H), 3.57-3.54 (m, 1H), 3.50-3.41 (m, 1H), 3.40-3.30 (m, 1H),3.28-3.13 (m, 1H), 2.15 (s, 3H), 1.81-1.71 (m, 1H), 1.70-1.59 (m, 3H),1.48-1.45 (m, 1H), 1.37- 1.32 (m, 1H). AVG-053

424.1 2.78 10.32 C (CDCl₃) δ 9.85 (s, 1H), 7.60 (s, 1H), 7.52 (d, J =8.8 Hz, 1H), 7.36 (dd, J = 7.6, 1.6 Hz, 1H), 7.26- 7.22 (m, 1H), 7.15(dd, J = 8.0, 7.6 Hz, 1H), 7.06 (ddd, J = 7.6, 7.6, 0.8 Hz, 1H), 7.01(d, J = 8.4 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 5.61 (d, J = 17.2 Hz,1H), 4.48 (s, 1H), 4.01 (d, J = 17.2 Hz, 1H), 3.70-3.57 (m, 2H),3.36-3.26 (m, 2H), 2.30 (s, 3H), 2.01-1.71 (m, 3H), 1.71-1.63 (m, 1H),1.53-1.29 (m, 2H). AVG-054

418 2.27 8.1 C (CDCl₃) δ 7.86 (d. J = 8.0 Hz, 1H), 7.34 (dd, J = 7.6,1.2 Hz, 1H), 7.31- 7.27 (m, 1H), 7.08 (ddd, J = 7.6, 7.4, 0.8 Hz, 1H),6.96 (dd, J = 8.2, 1.0 Hz, 1H), 5.39 (d, J = 17.2 Hz, 1H), 4.39 (s, 1H),3.90 (d, J = 17.2 Hz, 1H), 3.84-3.74 (m, 3H), 3.71-3.62 (m, 2H),3.59-3.49 (m, 2H), 3.47- 3.37 (m, 2H), 1.85-1.81 (m, 2H), 1.72-1.60 (m,2H), 1.48-1.22 (m, 3H), 1.19-1.01 (m, 3H). AVG-055

417.3 1.99 7.04 C (CDCl₃) δ 7.93 (d, J = 7.2 Hz, 1H), 7.34 (dd, J = 7.8,1.4 Hz, 1H), 7.31- 7.27 (m, 1H), 7.07 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H),6.95 (dd, J = 8.2, 1.0 Hz, 1H), 5.39 (d, J = 17.2 Hz, 1H), 4.41 (s, 1H),3.89 (d, J = 17.2 Hz, 1H), 3.84-3.75 (m, 1H), 3.66-3.54 (m, 2H),3.48-3.29 (m, 2H), 3.10- 2.94 (m, 2H), 2.87-2.83 (m, 1H), 2.76-2.67 (m,1H), 1.88-1.80 (m, 3H), 1.61-1.53 (m, 2H), 1.37- 1.24 (m, 2H), 1.19-1.01(m, 3H). AVG-056

431.1 1.77 6.44 C (DMSO-d₆) δ 7.96 (d, J = 8.0 Hz, 1H), 7.44 (dd, J =7.8, 1.4 Hz, 1H), 7.31 (ddd, J = 8.8, 8.4, 1.4 Hz, 1H), 7.08 (dd, J =7.2, 6.8 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 5.14 (s, 1H), 4.69 (d, J =16.8 Hz, 1H), 4.28 (d, J = 17.2 Hz, 1H), 3.63-3.52 (m, 2H), 3.48-3.38(m, 2H), 3.30 (s, 2H), 2.39- 2.28 (m, 3H), 2.18 (s, 3H), 1.72-1.61 (m,4H), 1.55-1.48 (m, 1H), 1.31- 1.17 (m, 2H), 1.13-1.01 (m, 3H). AVG-057

376.3 2.43 8.67 C (CDCl₃) δ 7.98 (d, J = 7.2 Hz, 1H), 7.31 (dd, J = 7.7,1.4 Hz, 1H), 7.25- 7.23 (m, 1H), 7.06 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H),6.95 (dd, J = 8.4, 0.8 Hz, 1H), 5.40 (d, J = 17.2 Hz, 1H), 4.40 (s, 1H),3.90 (d, J = 17.2 Hz, 1H), 3.83-3.75 (m, 1H), 3.14 (s, 3H), 2.88 (s,3H), 1.88-1.78 (m, 2H), 1.72-1.61 (m, 2H), 1.34-1.25 (m, 3H), 1.21- 1.12(m, 2H), 1.10-0.98 (m, 1H). AVG-058

430.2 2.8 10.4 C (CDCl₃) δ 7.45 (d, J = 8.0 Hz, 1H), 7.35 (dd, J = 7.8,1.4 Hz, 1H), 7.25- 7.22 (m, 1H), 7.06 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H),6.94 (dd, J = 8.4, 0.8 Hz, 1H), 6.35 (d, J = 7.6 Hz, 1H), 5.40 (d, J =16.8 Hz, 1H), 4.25 (s, 1H), 3.82-.378 (m, 2H), 3.55-3.53 (m, 1H), 1.92-1.90 (m, 1H), 1.78-1.64 (m, 5H), 1.52-1.48 (m, 2H), 1.34-1.28 (m, 5H),1.15-1.11 (m, 6H), 0.81- 0.77 (m, 1H). AVG-059

430.3 2.62 9.42 C (CDCl₃) δ 7.24 (dd, J = 7.8, 1.4 Hz, 1H), 7.24- 7.19(m, 1H), 7.06 (ddd, J = 7.6, 7.2, 0.8 Hz, 1H), 6.88 (ddd, J = 7.6, 6.8,0.8 Hz, 1H), 5.35-5.20 (m, 1H), 4.64-4.62 (m, 1H), 4.41-4.34 (m, 0.5H),4.25-4.18 (m, 1H), 3.85-3.69 (m, 1H), 3.56-3.47 (m, 1H), 3.45- 3.28 (m,2.5H), 2.94- 2.87 (m, 3H), 1.91-1.75 (m, 3H), 1.71-1.64 (m, 5H),1.55-1.50 (m, 4H), 1.43-1.32 (m, 3H), 1.14- 1.07 (m, 1H). AVG-060

402.1 2.27 8.65 C (CDCl₃) δ 7.42 (dd, J = 7.8, 1.4 Hz, 1H), 7.30 (ddd, J= 7.8, 7.4, 1.2 Hz, 1H), 7.07-6.97 (m, 1H), 6.89 (dd, J = 8.2, 1.0 Hz,1H), 5.26 (d, J = 16.2 Hz, 1H), 4.64 (s, 1H), 4.22 (d, J = 16.2 Hz, 1H),3.77-3.75 (m, 1H), 3.59-3.56 (m, 2H), 3.45-3.44 (m, 3H), 3.44- 3.34 (m,1H), 3.34-3.26 (m, 1H), 1.68-1.67 (m, 3H), 1.67-1.62 (m, 4H), 1.59-1.51(m, 4H), 1.26 (s, 1H). AVG-061

450.2 2.94 10.52 C (CDCl₃) δ 8.04 (d, J = 8.0 Hz, 1H), 7.23-7.14 (m,2H), 6.87 (dd, J = 8.0, 1.6 Hz, 1H), 5.38 (d, J = 17.2 Hz, 1H), 4.49 (s,1H), 3.86 (d, J = 17.2 Hz, 1H), 3.82-3.74 (m, 1H), 3.72-3.59 (m, 2H),3.39-3.24 (m, 1H), 3.21-3.07 (m, 1H), 1.91- 1.80 (m, 3H), 1.77-1.60 (m,5H), 1.56-1.48 (m, 2H), 1.43-1.26 (m, 3H), 1.20-1.04 (m, 3H). AVG-062

450.2 3 10.75 C (CDCl₃) δ 8.00 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 2.0 Hz,1H), 7.22 (dd, J = 8.8, 2.0 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 5.40 (d,J = 17.6 Hz, 1H), 4.43 (s, 1H), 3.89-3.75 (m, 2H), 3.61-3.48 (m, 2H),3.39-3.24 (m, 2H), 1.84-1.79 (m, 2H), 1.76- 1.61 (m, 6H), 1.56-1.40 (m,3H), 1.33-1.22 (m, 2H), 1.19-1.03 (m, 3H). AVG-063

450.2 2.86 10.29 C (CDCl₃) δ 7.98 (d, J = 7.6 Hz, 1H), 7.25 (s, 1H),7.03 (dd, J = 8.4, 2.0 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 5.37 (d, J =17.6 Hz, 1H), 4.42 (s, 1H), 3.91-3.75 (m, 2H), 3.63-3.50 (m, 2H), 3.37-3.20 (m, 2H), 1.98-1.78 (m, 2H), 1.78-1.58 (m, 7H), 1.55-1.49 (m, 1H),1.47-1.38 (m, 1H), 1.36- 1.24 (m, 2H), 1.21-1.04 (m, 3H). AVG-064

450.2 2.59 9.31 C (CDCl₃) δ 7.37 (d, J = 7.2 Hz, 1H), 7.34 (dd, J = 8.0,1.6 Hz, 1H), 7.05 (dd, J = 8.0, 7.6 Hz, 1H), 4.79 (d, J = 16.8 Hz, 1H),4.53-4.42 (m, 2H), 3.85-3.71 (m, 1H), 3.67- 3.21 (m, 4H), 1.94-1.75 (m,2H), 1.72-1.61 (m, 5H), 1.60-1.49 (m, 3H), 1.43-1.24 (m, 3H), 1.21- 1.08(m, 3H). AVG-083

432.3 2.2 8.32 C (CDCl₃) δ 7.37 (dd, J = 7.6, 1.6 Hz, 1H), 7.30- 7.27(m, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.07 (ddd, J = 7.6, 7.6, 0.8 Hz, 1H),6.94 (dd, J = 8.0, 0.8 Hz, 1H), 6.57 (d, J = 7.6 Hz, 1H), 5.37 (d, J =16.8 Hz, 1H), 4.26 (s, 1H), 3.90-3.74 (m, 5H), 3.46-3.22 (m, 2H),1.94-1.91 (m, 1H), 1.84-1.81 (m, 1H), 1.77- 1.64 (m, 3H), 1.63-1.58 (m,1H), 1.42-1.33 (m, 3H), 1.32-1.19 (m, 2H), 1.19-1.02 (m, 3H). AVG-084

431.3 1.80 6.30 C (CDCl₃) δ 7.37 (d, J = 7.6 Hz, 1H), 7.30-7.24 (m, 1H),7.11 (d, J = 7.6 Hz, 1H), 7.07 (dd, J = 7.6 Hz, 1H), 6.93 (d, J = 8.0Hz, 1H), 6.80 (d, J = 8.0 Hz, 1H), 5.36 (d, J = 16.8 Hz, 1H), 4.26 (s,1H), 3.86 (d, J = 16.8 Hz, 1H), 3.86-3.66 (m, 2H), 3.07-2.96 (m, 2H),2.73-2.58 (m, 2H), 1.95- 1.56 (m, 5H), 1.52-1.07 (m, 9H). AVG-085

445.3 2.07 7.40 C (CDCl₃) δ 7.36 (d, J = 7.6 Hz, 1H), 7.30-7.26 (m, 1H),7.26-7.23 (m, 1H), 7.06 (dd, J = 7.6, 7.2 Hz, 1H), 6.93 (d, J = 8.4 Hz,1H), 6.49 (d, J = 8.0 Hz, 1H), 5.38 (d, J = 16.8 Hz, 1H), 4.26 (s, 1H),3.88-3.76 (m, 2H), 3.62-3.50 (m, 1H), 2.74- 2.65 (m, 1H), 2.61-2.50 (m,1H), 2.23 (s, 3H), 2.10-2.00 (m, 1H), 1.98- 1.88 (m, 2H), 1.84-1.64 (m,4H), 1.47-1.05 (m, 9H). AVG-086

404.3 2.69 9.63 C (CDCl₃) δ 7.45 (d, J = 8.0 Hz, 1H), 7.35 (dd, J = 7.8,1.4 Hz, 1H), 7.26- 7.23 (m, 1H), 7.06 (ddd, J = 7.6, 7.2, 0.8 Hz, 1H),6.94 (d, J = 8.4 Hz, 1H), 6.52 (s, 1H), 5.42 (d, J = 17.2 Hz, 1H), 4.27(s, 1H), 3.88-3.75 (m, 2H), 3.28-3.24 (m, 1H), 3.03- 2.9 (m, 1H),1.94-1.91 (m, 1H), 1.82-1.78 (m, 1H), 1.75-1.65 (m, 2H), 1.38-1.27 (m,4H), 1.19- 1.04 (m, 3H), 1.02-0.79 (m, 3H), 0.73 (t, J = 7.2 Hz, 3H).AVG-087

390.3 2.56 9.19 C (CDCl₃) δ 7.48 (d, J = 7.6 Hz, 1H), 7.36 (dd, J = 7.6,1.2 Hz, 1H), 7.26- 7.22 (m, 1H), 7.06 (ddd, J = 8.0, 7.6, 0.6 Hz, 1H),6.94 (d, J = 8.4 Hz, 1H), 6.31 (d, J = 8.0 Hz, 1H), 5.40 (d, J = 17.2Hz, 1H), 4.24 (s, 1H), 3.90- 3.74 (m, 3H), 1.96-1.88 (m, 1H), 1.84-1.76(m, 1H), 1.75-1.65 (m, 2H), 1.43-1.27 (m, 4H), 1.19- 1.10 (m, 2H),1.09-1.07 (m, 3H), 0.76 (d, J = 6.4 Hz, 3H). AVG-111

408.2 2.60 9.24 C (CDCl₃) δ 7.71-7.67 (m, 1H), 7.53-7.49 (m, 1H), 4.42(dd, J = 7.6 Hz, 0.8 Hz, 1H), 7.36-7.31 (m, 2H), 7.26-7.23 (m, 2H),7.07-7.03 (m, 1H), 5.72 (d, J = 16.8 Hz, 1H), 5.21 (d, J = 17.2 Hz, 1H),4.66 (s, 1H), 3.66- 3.58 (m, 1H), 3.54-3.34 (m, 3H), 1.71-1.58 (m, 4H),1.58-1.43 (m, 2H). AVG-112

407.2 2.53 9.00 C (CDCl₃) δ 11.73 (brs, 1H), 7.75 (d, J = 8.0 Hz, 1H),7.40 (d, J = 7.6 Hz, 1H), 7.36 (dd, J = 7.8, 1.4 Hz, 1H), 7.26-7.17 (m,2H), 7.13 (ddd, J = 8.2, 7.6, 1.6 Hz, 1H), 7.03 (ddd, J = 8.0, 7.6, 0.8Hz, 1H), 6.87 (dd, J = 8.0, 0.8 Hz, 1H), 6.30 (d, J = 17.2 Hz, 1H), 4.85(d, J = 17.2 Hz, 1H), 4.54 (s, 1H), 3.72- 3.57 (m, 2H), 3.46-3.33 (m,2H), 1.87-1.60 (m, 5H), 1.49-1.38 (m, 1H). AVG-113

334.2 1.96 7.38 C (CDCl₃) δ 8.29 (s, 1H), 7.38-7.32 (m, 1H), 7.29- 7.27(m, 1H), 7.08 (dd, J = 7.6, 7.6 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H),5.51-5.24 (m, 2H), 4.44 (s, 1H), 3.91 (d, J = 17.5 Hz, 1H), 3.60-3.47(m, 2H), 3.41-3.32 (m, 1H), 3.29-3.20 (m, 1H), 1.87- 1.72 (m, 1H),1.72-1.62 (m, 3H), 1.53-1.45 (m, 1H), 1.42-1.30 (m, 1H). AVG-114

374.2 2.34 8.4 C (CDCl₃) δ 8.32 (s, 1H), 7.33 (dd, J = 7.8, 1.4 Hz, 1H),7.30-7.27 (m, 1H), 7.06 (ddd, J = 7.6, 7.4, 1.0 Hz, 1H), 6.92 (dd, J =8.4, 0.8 Hz, 1H), 5.42 (d, J = 17.6 Hz, 1H), 4.40 (s, 1H), 3.90 (d, J =17.6 Hz, 1H), 3.64-3.47 (m, 2H), 3.42- 3.16 (m, 2H), 2.91-2.77 (m, 1H),1.81-1.72 (m, 1H), 1.72-1.61 (m, 3H), 1.56-1.47 (m, 1H), 1.43- 1.32 (m,1H), 0.76-0.60 (m, 2H), 0.60-0.37 (m, 2H). AVG-137

424.3 2.62 9.31 C (DMSO-d₆) δ 8.72 (t, J = 5.8 Hz, 1H), 7.45 (dd, J =8.0, 1.6 Hz, 1H), 7.33- 7.27 (m, 3H), 7.23-7.20 (m, 3H), 7.09 (dd, J =7.6, 7.2 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 5.14 (s, 1H), 4.68 (d, J =17.2 Hz, 1H), 4.51 (d, J = 16.8 Hz, 2H), 4.32 (d, J = 6.0 Hz, 2H), 3.51-3.41 (m, 2H), 3.26-3.20 (m, 2H), 1.55-1.52 (m, 4H), 1.44-1.42 (m, 1H),1.30-1.28 (m, 1H) AVG-138

438.2 2.76 9.75 C (DMSO-d₆) δ 8.75-8.55 (m, 1H), 7.31-7.23 (m, 1.5H),7.23-7.19 (m, 2H), 7.16-7.08 (m, 3H), 7.06-6.92 (m, 2H), 6.65- 6.62 (m,0.5H), 5.41- 5.34 (m, 1H), 5.11-5.02 (m, 1H), 4.38 (s, 1H), 3.89-3.76(m, 1H), 3.54- 3.40 (m, 2H), 3.35-3.12 (m, 2H), 1.75-1.53 (m, 4H),1.45-1.25 (m, 5H) AVG-139

452.3 2.90 10.15 C (DMSO-d₆) δ 8.35 (s, 1H), 7.45 (dd, J = 7.8, 1.2 Hz,1H), 7.36 (dd, J = 7.8, 1.2 Hz, 1H), 7.31- 7.24 (m, 4H), 7.18-7.17 (m,1H), 7.10 (dd, J = 7.6, 7.2 Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 5.14 (s,1H), 4.74 (d, J = 17.2 Hz, 1H), 4.30 (d, J = 16.8 Hz, 1H), 3.55-3.51 (m,1H), 3.44-3.39 (m, 2H), 3.26-3.21 (m, 1H), 1.58-1.52 (m, 6H), 148- 1.42(m, 4H), 1.28-1.26 (m, 2H) AVG-140

390.3 2.66 9.48 C (CDCl₃) δ 7.68 (s, 1H), 7.32 (dd, J = 7.8, 1.4 Hz,1H), 7.31-7.27 (m, 1H), 7.06 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 6.96 (dd,J = 8.4, 0.8 Hz, 1H), 5.34 (d, J = 17.2 Hz, 1H), 4.41 (s, 1H), 3.80 (d,J = 17.2 Hz, 1H), 3.58-3.48 (m, 2H), 3.38- 3.18 (m, 2H), 1.86-1.61 (m,4H), 1.59 (s, 9H), 1.54-1.46 (m, 1H), 1.43- 1.37 (m, 1H). AVG-141

404.2 2.69 9.97 C (CDCl₃) δ 7.70 (d, J = 7.2 Hz, 1H), 7.37 (dd, J = 7.6,1.2 Hz, 1H), 7.30- 7.28 (m, 1H), 7.07 (ddd, J = 7.6, 7.6, 0.8 Hz, 1H),6.94 (dd, J = 8.4, 0.8 Hz, 1H), 6.28 (s, 1H), 5.42 (d, J = 17.2 Hz, 1H),4.22 (s, 1H), 3.88- 3.73 (m, 2H), 2.01-1.86 (m, 1H), 1.80-1.65 (m, 3H),1.41-1.18 (m, 4H), 1.17-1.09 (m, 2H), 1.09 (s, 9H). AVG-142

438.3 2.66 9.35 C (DMSO-d₆) δ 8.98 (t, J = 5.8 Hz, 1H), 7.95 (d, J = 8.0Hz, 1H), 7.45 (dd, J = 7.6, 1.2 Hz, 1H), 7.33 (ddd, J = 8.4, 8.4, 1.2Hz, 1H), 7.17 (m, 3H), 7.12 (dd, J = 8.0, 7.2 Hz, 1H), 6.94-6.90 (m,3H), 4.85 (d, J = 17.2 Hz, 1H), 4.58 (s, 1H), 4.24-4.20 (m, 3H), 3.55-3.52 (m, 1H), 1.64-1.57 (m, 3H), 1.51-1.48 (m, 2H), 1.22-1.15 (m, 2H),1.09-0.99 (m, 3H) AVG-143

452.3 2.79, 2.86 9.68, 9.88 C (DMSO-d₆) δ 7.40-7.26 (m, 4H), 7.17-6.95(m, 4H), 6.90-6.78 (m, 2H), 6.67(d, J = 7.6 Hz, 1H), 5.46-5.38 (m, 1H),4.92- 4.84 (m, 1H), 4.34-4.26 (m, 1H), 3.87-3.65 (m, 2H), 1.92-1.62 (m,3H), 1.58-1.40 (m, 4H), 1.36- 1.05 (m, 5H), 0.75-0.60 (m, 1H). AVG-144

466.2 2.79 10.31 C (CDCl₃) δ 7.51 (dd, J = 7.6, 1.6 Hz, 1H), 7.43- 7.31(m, 2H), 7.20 (ddd, J = 7.6, 7.6, 1.0 Hz, 1H), 7.11-6.96 (m, 3H), 6.89(dd, J = 8.4, 0.8 Hz, 1H), 6.85 (s, 1H), 6.76-6.72 (m, 2H), 5.42 (d, J =16.8 Hz, 1H), 4.29 (s, 1H), 3.72 (d, J = 16.8 Hz, 1H), 3.67-3.52 (m,1H), 1.80-1.68 (m, 1H), 1.63 (s, 3H), 1.57-1.53 (m, 1H), 1.52-1.42 (m,2H), 1.41 (s, 3H), 1.34- 1.26 (m, 1H), 1.25-1.08 (m, 2H), 1.01-0.80 (m,2H), 0.51-0.32 (m, 1H). AVG-145

446.3 2.79 9.88 C (CDCl₃) δ 8.10 (d, J = 7.6 Hz, 1H), 7.20 (dd, J = 8.4,8.0 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 5.39(d, J = 17.2 Hz, 1H), 4.43 (s, 1H), 3.94-3.84 (m, 4H), 3.83-3.73 (m,1H), 3.67-3.45 (m, 2H), 3.45-3.20 (m, 2H), 1.90- 1.74 (m, 3H), 1.72-1.61(m, 5H), 1.55-1.48 (m, 2H), 1.48-1.38 (m, 1H), 1.37-1.25 (m, 2H), 1.22-1.12 (m, 2H), 1.11-1.03 (m, 1H). AVG-146

446.3 2.78 9.67 C (CDCl₃) δ 8.00 (d, J = 8.0 Hz, 1H), 6.88-6.84 (m, 2H),6.78 (dd, J = 8.8, 2.8 Hz, 1H), 5.37 (d, J = 17.2 Hz, 1H), 4.40 (s, 1H),3.86-3.76 (m, 5H), 3.60-3.49 (m, 2H), 3.38-3.25 (m, 2H), 1.87-1.80 (m,2H), 1.76- 1.61 (m, 6H), 1.57-1.38 (m, 2H), 1.37-1.25 (m, 3H), 1.20-1.03(m, 3H). AVG-147

446.2 2.87 10.12 C (CDCl₃) δ 7.94 (d, J = 7.2 Hz, 1H), 7.14 (d, J = 8.4Hz, 1H), 6.54 (dd, J = 8.4, 2.4 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 5.29(d, J = 17.2 Hz, 1H), 4.29 (s, 1H), 3.81 (d, J = 17.2 Hz, 1H), 3.77-3.67(m, 1H), 3.70 (s, 3H), 3.57-3.44 (m, 2H), 3.29- 3.21 (m, 1H), 3.19-3.11(m, 1H), 1.84-1.70 (m, 2H), 1.68-1.54 (m, 5H), 1.51-1.42 (m, 2H), 1.37-1.16 (m, 4H), 1.15-0.95 (m, 3H). AVG-148

446.3 2.61 9.29 C (CDCl₃) δ 7.07-6.95 (m, 3H), 6.84 (dd, J = 8.0, 1.2Hz, 1H), 4.83 (d, J = 16.4 Hz, 1H), 4.39 (s, 1H), 4.16 (d, J = 17.6 Hz,1H), 3.82 (s, 3H), 3.82-3.74 (m, 1H), 3.66- 3.50 (m, 2H), 3.34-3.17 (m,2H), 1.93-1.80 (m, 2H), 1.72-1.63 (m, 5H), 1.60-1.49 (m, 2H), 1.38- 1.24(m, 4H), 1.23-1.09 (m, 3H). AVG-149

494.2 3.133 10.91 C (CDCl₃) δ 7.99 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 2.4Hz, 1H), 7.36 (dd, J = 8.8, 2.0 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 5.39(d, J = 17.2 Hz, 1H), 4.42 (s, 1H), 3.83 (d, J = 17.2 Hz, 1H), 3.79-3.74(m, 1H), 3.59-3.49 (m, 2H), 3.38-3.27 (m, 2H), 1.83-1.80 (m, 2H), 1.76-1.62 (m, 6H), 1.56-1.55 (m, 2H), 1.49-1.43 (m, 1H), 1.36-1.25 (m, 2H),1.19-1.06 (m, 3H). AVG-150

434.3 2.90 10.18 C (CDCl₃) δ 7.99 (d, J = 7.6 Hz, 1H), 7.07 (dd, J =7.8, 3.0 Hz, 1H), 6.97 (ddd, J = 8.8, 8.0, 2.8 Hz, 1H), 6.90 (dd, J =9.2, 4.4 Hz, 1H), 5.39 (d, J = 17.2 Hz, 1H), 4.43 (s, 1H), 3.84 (d, J =17.2 Hz, 1H), 3.83-3.74 (m, 1H), 3.61-3.50 (m, 2H), 3.37-3.24 (m, 2H),1.87-1.78 (m, 2H), 1.76- 1.63 (m, 6H), 1.60-1.51 (m, 2H), 1.48-1.38 (m,1H), 1.37-1.24 (m, 2H), 1.20-1.03 (m, 3H). AVG-151

430.3 2.92 10.38 C (CDCl₃) δ 8.01 (d, J = 7.2 Hz, 1H), 7.12 (s, 1H),7.05 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.38 (d, J = 17.2Hz, 1H), 4.40 (s, 1H), 3.85 (d, J = 17.2 Hz, 1H), 3.83-3.78 (m, 1H),3.60-3.48 (m, 2H), 3.39- 3.23(m, 2H), 2.29 (s, 3H), 1.87-1.78 (m, 2H),1.77-1.61 (m, 6H), 1.57- 1.49 (m, 2H), 1.48-1.37 (m, 1H), 1.36-1.23 (m,2H), 1.20-1.01 (m, 3H). AVG-152

444.3 3.05 10.69 C (CDCl₃) δ 8.02 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 2.0Hz, 1H), 7.07 (dd, J = 8.4, 2.0 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 5.37(d, J = 17.2 Hz, 1H), 4.40 (s, 1H), 3.87 (d, J = 17.2 Hz, 1H), 3.83-3.72(m, 1H), 3.63-3.42 (m, 2H), 3.42-3.20 (m, 2H), 2.62-2.57 (m, 2H), 1.88-1.80 (m, 2H), 1.79-1.71 (m, 1H), 1.71-1.62 (m, 5H), 1.57-1.49 (m, 2H),1.47-1.38 (m, 1H), 1.37- 1.25 (m, 2H), 1.22 (t, J = 7.6 Hz, 3H),1.19-1.01 (m, 3H). AVG-153

458.3 3.19 10.95 C (CDCl₃) δ 8.01 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 2.0Hz, 1H), 7.09 (dd, J = 8.6, 1.8 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 5.36(d, J = 17.2 Hz, 1H), 4.40 (s, 1H), 3.87 (d, J = 17.2 Hz, 1H), 3.83-3.72(m, 1H), 3.63-3.45 (m, 2H), 3.43-3.21 (m, 2H), 2.91-2.77 (m, 1H), 1.91-1.79 (m, 2H), 1.78-1.71 (m, 1H), 1.71-1.59 (m, 5H), 1.57-1.47 (m, 2H),1.45-1.36 (m, 1H), 1.35- 1.25 (m, 2H), 1.23 (d, J = 7.2 Hz, 6H),1.18-1.10 (m, 2H), 1.10-0.99 (m, 1H). AVG-154

492.3 3.15 11.08 C (CDCl₃) δ 8.07 (d, J = 7.6 Hz, 1H), 7.60-7.52 (m,3H), 7.51-7.41 (m, 3H), 7.39-7.33 (m, 1H), 7.01 (d, J = 8.4 Hz, 1H),5.42 (d, J = 17.6 Hz, 1H), 4.46 (s, 1H), 3.93 (d, J = 17.6 Hz, 1H),3.86-3.73 (m, 1H), 3.60- 3.49 (m, 2H), 3.41-3.24 (m, 2H), 1.91-1.78 (m,2H), 1.77-1.61 (m, 6H), 1.53-1.42 (m, 2H), 1.40- 1.22 (m, 3H), 1.22-1.01(m, 3H). AVG-155

417.3 2.39 8.59 C (CDCl₃) δ 8.50 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 8.05(d, J = 7.2 Hz, 1H), 6.82 (d, J = 6.0 Hz, 1H), 5.43 (d, J = 17.6 Hz,1H), 4.49 (s, 1H), 3.87 (d, J = 17.6 Hz, 1H), 3.81-3.72 (m, 1H), 3.61-3.50 (m, 2H), 3.41-3.23 (m, 2H), 1.88-1.74 (m, 3H), 1.74-1.60 (m, 6H),1.54-1.37 (m, 2H), 1.35- 1.26 (m, 2H), 1.18-1.02 (m, 3H). AVG-156

484.2 2.94 10.77 C (CDCl₃) δ 8.00 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 1.6Hz, 1H), 7.51 (dd, J = 8.8, 1.6 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 5.43(d, J = 17.6 Hz, 1H), 4.48 (s, 1H), 3.89 (d, J = 17.6 Hz, 1H), 3.84-3.73(m, 1H), 3.61-3.48 (m, 2H), 3.41-3.25 (m, 2H), 1.83 (d, J = 12.1 Hz,2H), 1.78-1.61 (m, 6H), 1.56-1.47 (m, 2H), 1.47- 1.39 (m, 1H), 1.37-1.26(m, 2H), 1.19-1.03 (m, 3H). AVG-182

423.2 2.52 8.82 C (CDCl₃) δ11.65 (brs, 1H), 7.76 (d, J = 6.8 Hz, 1H),7.45-7.34 (m, 2H), 7.26-7.14 (m, 3H), 7.08 (dd, J = 7.6, 7.2 Hz, 1H),7.00-6.91 (m, 1H), 6.26- 6.08 (m, 1H), 5.65 (brs, 1H), 5.03 (d, J = 16.4Hz, 1H), 4.06-3.97 (m, 1H), 3.83-3.75 (m, 1H), 3.59-3.51 (m, 1H), 3.43-3.34 (m, 1H), 1.82-1.60 (m, 4H), 1.60-1.52 (m, 1H), 1.44-1.34 (m, 1H).AVG-215

456.3 3.15 10.82 C (CDCl₃) δ 8.03 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 1.6Hz, 1H), 7.35 (dd, J = 8.8, 1.6 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H),5.46-5.35 (m, 2H), 5.10 (s, 1H), 4.42 (s, 1H), 3.88 (d, J = 16.8 Hz,1H), 3.83-3.75 (m, 1H), 3.57-3.50 (m, 2H), 3.39- 3.29 (m, 2H), 2.12 (s,3H), 1.93-1.80 (m, 2H), 1.78-1.62 (m, 6H), 1.61- 1.58 (m, 1H), 1.51-1.39(m, 2H), 1.34-1.26 (m, 2H), 1.20-1.04 (m, 3H). AVG-216

430.3 2.83 10.421 C (CDCl₃) δ 8.19 (brs, 1H), 7.33 (dd, J = 8.0, 1.6 Hz,1H), 7.29-7.25 (m, 1H), 7.06 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 6.95 (d, J= 8.0 Hz, 1H), 5.42 (d, J = 17.6 Hz, 1H), 4.42 (s, 1H), 3.92 (d, J =17.2 Hz, 2H), 3.56-3.49 (m, 2H), 3.39- 3.33 (m, 1H), 3.30-3.24 (m, 1H),3.22-3.16 (m, 1H), 3.06-3.00 (m, 1H), 1.78-1.62 (m, 9H), 1.55- 1.35 (m,3H), 1.17-1.08 (m, 3H), 0.89-0.80 (m, 2H). AVG-217

464.3 3.21 11.23 C (DMSO-d₆) δ 8.11 (t, J = 5.6 Hz, 1H), 7.57 (d, J =2.4 Hz, 1H), 7.36 (dd, J = 8.6, 2.2 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H),5.19 (s, 1H), 4.65 (d, J = 17.2 Hz, 1H), 4.36 (d, J = 17.2 Hz, 1H),3.54-3.26 (m, 4H), 2.99-2.87(m, 2H), 1.66-1.49 (m, 9H), 1.48-1.26 (m,3H), 1.18- 1.01 (m, 3H), 0.88-0.72 (m, 2H). AVG-218

464.2 3.18 11.10 C (CDCl₃) δ 7.43 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 2.4Hz, 1H), 7.23 (dd, J = 9.2, 2.4 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.30(d, J = 8.0 Hz, 1H), 5.40 (d, J = 17.2 Hz, 1H), 4.25 (s, 1H), 3.85-3.74(m, 2H), 3.63-3.52 (m, 1H), 1.94-1.87 (m, 1H), 1.82-1.63 (m, 5H), 1.62-1.51 (m, 2H), 1.44-1.05 (m, 11H), 0.95-0.84 (m, 1H). AVG-219

458.2 3.01 10.55 C (CDCl₃) δ 9.53 (s, 1H), 7.40 (d, J = 7.6 Hz, 1H),7.36 (d, J = 2.4 Hz, 1H), 7.31-7.27 (m, 1H), 7.22- 7.14 (m, 2H),7.13-7.09 (m, 1H), 7.06 (d, J = 8.4 Hz, 1H), 5.63 (d, J = 17.2 Hz, 1H),4.49 (s, 1H), 4.04 (d, J = 17.2 Hz, 1H), 3.56-3.36 (m, 3H), 3.33-3.20(m, 1H), 2.14 (s, 3H), 1.79-1.60 (m, 4H), 1.52-1.46 (m, 1H), 1.45-1.33(m, 1H). AVG-220

444.2 2.82 9.86 C (CDCl₃) δ 9.64 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H),7.40-7.34 (m, 2H), 7.33- 7.30 (m, 1H), 7.25-7.21 (m, 2H), 7.14-7.07 (m,2H), 5.51 (d, J = 17.2 Hz, 1H), 4.49 (s, 1H), 4.23 (d, J = 17.6 Hz, 1H),3.59-3.45 (m, 2H), 3.39-3.28 (m, 1H), 3.28- 3.14 (m, 1H), 1.78-1.59 (m,5H), 1.39-1.25 (m, 1H). AVG-221

440.3 2.67 9.46 C (CDCl₃) δ 9.06 (s, 1H), 7.99 (d, J = 6.8 Hz, 1H), 7.37(d, J = 7.6 Hz, 1H), 7.32-7.27 (m, 1H), 7.20 (d, J = 8.4 Hz, 1H),7.12-7.04 (m, 2H), 6.93 (dd, J = 7.6, 7.6 Hz, 1H), 6.84 (d, J = 8.0 Hz,1H), 5.28 (d, J = 18.0 Hz, 1H), 4.53 (s, 1H), 4.38 (d, J = 16.4 Hz, 1H),3.75 (s, 3H), 3.57-3.48 (m, 2H), 3.38-3.29 (m, 2H), 1.73-1.60 (m, 4H),1.52-1.47 (m, 1H), 1.45- 1.35 (m, 1H). AVG-222

441.2 2.46 8.71 C (CDCl₃) δ 10.08 (s, 1H), 8.31 (dd, J = 4.6, 1.0 Hz,1H), 8.21 (d, J = 8.4 Hz, 1H), 7.68 (ddd, J = 8.8, 8.8, 1.8 Hz, 1H),7.35 (dd, J = 7.6, 1.2 Hz, 1H), 7.31-7.27 (m, 1H), 7.10-6.96 (m, 3H),5.59 (d, J = 17.6 Hz, 1H), 4.51 (s, 1H), 4.12 (d, J = 17.6 Hz, 1H),3.80-3.73 (m, 1H), 3.65- 3.58 (m, 1H), 3.36-3.21 (m, 2H), 1.79-1.65 (m,2H), 1.63-1.60 (m, 2H), 1.46-1.24 (m, 2H). AVG-223

411.2 2.45 8.57 C (DMSO-d₆) δ 10.35 (s, 1H), 8.75 (d, J = 2.4 Hz, 1H),8.28 (m, J = 3.2 Hz, 1H), 8.06 (dd, J = 6.8, 1.6 Hz, 1H), 7.48 (dd, J =7.6, 1.2 Hz, 1H), 7.38- 7.29 (m, 2H), 7.14-7.08 (m, 2H), 5.22 (s, 1H),4.91 (d, J = 17.6 Hz, 1H), 4.66 (d, J = 17.6 Hz, 1H), 3.56-3.49 (m, 2H),3.39-3.38 (m, 2H), 1.57-1.47 (m, 4H), 1.32- 1.29 (m, 2H) AVG-224

441.2 2.37 8.47 C (CDCl₃) δ 10.24 (s, 1H), 8.45 (s, 2H), 7.72 (d, J =4.8 Hz, 2H), 7.38 (dd, J = 7.8, 1.4 Hz, 1H), 7.32- 7.28 (m, 1H), 7.09(dd, J = 7.6, 7.6 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 5.63 (d, J = 18.0Hz, 1H), 4.50 (s, 1H), 4.03 (d, J = 17.6 Hz, 1H), 3.80-3.60 (m, 2H),3.48-3.23 (m, 2H), 1.85-1.64 (m, 4H), 1.56-1.21 (m, 2H).

Example 4: Potency Range of Certain Compounds (EC50 Values)

The potency range of selected compounds (EC50 values) was tested and theresults are provided below:

Potency Compound # Range* AVG-044 B AVG-045 D AVG-046 D AVG-047 DAVG-048 D AVG-049 B AVG-050 B AVG-051 B AVG-052 B AVG-053 D AVG-054 BAVG-055 D AVG-056 C AVG-057 B AVG-058 B AVG-059 D AVG-060 D AVG-061 BAVG-062 A AVG-063 B AVG-064 C AVG-083 D AVG-084 D AVG-085 D AVG-086 CAVG-087 C AVG-111 D AVG-112 C AVG-113 D AVG-114 D AVG-137 B AVG-138 BAVG-139 B AVG-140 B AVG-141 B AVG-142 C AVG-143 D AVG-144 B AVG-145 BAVG-146 B AVG-147 C AVG-148 C AVG-149 B AVG-150 B AVG-151 C AVG-152 BAVG-153 B AVG-154 D AVG-155 B AVG-156 B AVG-182 D AVG-215 B AVG-216 BAVG-217 B AVG-218 B AVG-219 A AVG-220 B AVG-221 B AVG-223 C AVG-224 C*Potency Range (EC50 values) A >0.1-1.0 μM B >1.0-10.0 μM C >10.0-20.0μM D >20.0 μM

What is claimed is:
 1. A method of inhibiting RSV, comprisingadministering to a patient in need thereof, an effective amount of acompound of Formula 1:

or a pharmaceutically acceptable salt thereof, wherein X is selectedfrom O, S, or NR⁷; z is selected from 0, 1, 2, 3, 4, 5, and 6; y isselected from 0, 1, 2, 3, 4, 5, and 6; R¹ and R² are independentlyselected from R^(a), OR^(a), N(R^(a))₂, SR^(a), C(═O)R^(a), C(═O)OR^(a),C(═O)N(R^(a))₂, C(═O)SR^(a); R³, R⁴, R⁵, and R⁶ are independentlyselected from independently selected from —R^(a), —OR^(a), —N(R^(a))₂,—SR^(a), —SO₂R^(a), —SO₂N(R^(a))₂; —C(O)R^(a), OC(O)R^(a), —COOR^(a),—C(O)N(R^(a))₂, —OC(O)N(R^(a))₂, —N(R^(a))C(O), —N(R^(a))C(O)N(R^(a))₂,—F, —Cl, —Br, —I, —CN, —NO₂; wherein when multiple R^(a) groups arepresent, said R^(a) groups may together form a ring; R⁷, when present,is R^(a), C(O)R^(a), SO₂R^(a), COOR^(a), C(O)N(R^(a))₂, wherein eitherof R³ and R⁴, or R⁵ and R⁶ may together form a double bond whereineither of R⁴ and R⁶ or R³ and R⁵ may together form a carbonyl, imine orolefin; and wherein any of two or more of R¹, R², R³, R⁴, R⁵, R⁶ or R⁷,or R^(a) groups may together form a ring; and wherein R^(a) is in eachcase independently selected from hydrogen, C₁₋₈ alkyl, C₃₋₈ cycloalkyl,C₂₋₈ heterocyclyl, C₆₋₁₂ aryl, C₃₋₁₂ heteroaryl, C₁₋₈ alkyl-C₃₋₈cycloalkyl, C₁₋₈ alkyl-C₂₋₈ heterocyclyl, C₁₋₈ alkyl-C₆₋₁₂ aryl, andC₁₋₈ alkyl-C₃₋₁₂ heteroaryl.
 2. The method according to claim 1, whereinX is S.
 3. The method according to claim 1, wherein R³ and R⁴ togetherform a ring.
 4. The method according to claim 1, wherein R³ and R⁴together form an aryl or heteroaryl ring.
 5. The method according toclaim 1, wherein R³ and R⁴ can together form a phenyl ring, to give acompound of Formula 1b or 1b-i:

wherein a is selected from 0, 1, 2, 3 and 4; and R⁸ is independentlyselected from —R^(a), —OR^(a), —N(R^(a))₂, —SR^(a), —SO₂R^(a),—SO₂N(R^(a))₂; —C(O)R^(a), OC(O)R^(a), —COOR^(a), —C(O)N(R^(a))₂,—OC(O)N(R^(a))₂, —N(R^(a))C(O), —N(R^(a))C(O)N(R^(a))₂, —F, —Cl, —Br,—I, —CN, —NO₂, wherein R^(a) has the meanings as set forth in claim 1.6. The method according to claim 1, wherein z is
 0. 7. The methodaccording to claim 1, wherein y is
 1. 8. The method according to claim1, wherein R¹ is N(R^(a))₂.
 9. The method according to claim 1, whereinR¹ is selected from

b is selected from 0, 1, 2, 3 and
 4. R⁹ is independently selected from—R^(a), —OR^(a), —N(R^(a))₂, —SR^(a), —SO₂R^(a), —SO₂N(R^(a))₂;—C(O)R^(a), OC(O)R^(a), —COOR^(a), —C(O)N(R^(a))₂, —OC(O)N(R^(a))₂,—N(R^(a))C(O), —N(R^(a))C(O)N(R^(a))₂, —F, —Cl, —Br, —I, —CN, —NO₂,wherein R^(a) has the meanings given above, and any two or more R⁹groups may together form a ring; wherein R¹⁰ when present, isindependently selected from R^(a), C(O)R^(a), SO₂R^(a), COOR^(a),C(O)N(R^(a))₂, wherein R¹⁰ may, with any one or more of R¹, R², R³, R⁴,R⁵, R⁶ or R⁷, R⁸, or R^(a) groups, together form a ring.
 10. The methodaccording to claim 1, wherein R¹ is a group of the formula:


11. The method according to claim 1, wherein R² is C(═O)NHR^(a1),wherein said R^(a1) is selected from C₃₋₈ cycloalkyl, C₂₋₈ heterocyclyl,C₆₋₁₂ aryl, and C₃₋₁₂ heteroaryl.
 12. The method according to claim 1,wherein R² is C(═O)NH—C₃₋₈ cycloalkyl.
 13. The method according to claim1, wherein R² is C(═O)NHcyclohexyl.
 14. The method according to claim 1wherein the compound of formula 1 is:


15. A method of treating or preventing an RSV infection, comprisingadministering to a patient in need thereof, an effective amount of acompound of Formula 1:

or a pharmaceutically acceptable salt thereof, wherein X is selectedfrom O, S, or NR⁷; z is selected from 0, 1, 2, 3, 4, 5, and 6; y isselected from 0, 1, 2, 3, 4, 5, and 6; R¹ and R² are independentlyselected from R^(a), OR^(a), N(R^(a))₂, SR^(a), C(═O)R^(a),—C(═O)OR^(a), C(═O)N(R^(a))₂, C(═O)SR^(a); R³, R⁴, R⁵, and R⁶ areindependently selected from independently selected from —R^(a), —OR^(a),—N(R^(a))₂, —SR^(a), —SO₂R^(a), —SO₂N(R^(a))₂; —C(O)R^(a), OC(O)R^(a),—COOR^(a), —C(O)N(R^(a))₂, —OC(O)N(R^(a))₂, —N(R^(a))C(O),—N(R^(a))C(O)N(R^(a))₂, —F, —Cl, —Br, —I, —CN, —NO₂; wherein whenmultiple R^(a) groups are present, said R^(a) groups may together form aring; R⁷, when present, is R^(a), C(O)R^(a), SO₂R^(a), COOR^(a),C(O)N(R^(a))₂, wherein either of R³ and R⁴, or R⁵ and R⁶ may togetherform a double bond wherein either of R⁴ and R⁶ or R³ and R⁵ may togetherform a carbonyl, imine or olefin; and wherein any of two or more of R¹,R², R³, R⁴, R⁵, R⁶ or R⁷, or R^(a) groups may together form a ring; andwherein R^(a) is in each case independently selected from hydrogen, C₁₋₈alkyl, C₃₋₈ cycloalkyl, C₂₋₈ heterocyclyl, C₆₋₁₂ aryl, C₃₋₁₂ heteroaryl,C₁₋₈ alkyl-C₃₋₈ cycloalkyl, C₁₋₈ alkyl-C₂₋₈ heterocyclyl, C₁₋₈alkyl-C₆₋₁₂ aryl, and C₁₋₈ alkyl-C₃₋₁₂ heteroaryl.
 16. The method oftreating or preventing an RSV infection according to claim 15 whereinthe compound is administered via a route of administration selected fromthe group consisting of buccal, oral, intravenous, inhalation,intradermal, intramuscular, topical, subcutaneous, rectal, vaginal,parenteral, pulmonary, intranasal, and ophthalmic.
 17. The method oftreating or preventing an RSV infection according to claim 15 whereinthe compound of Formula 1 is selected from the group consisting of:


18. The method of treating or preventing an RSV infection according toclaim 15 wherein the compound of Formula 1 is:


19. A compound of Formula 1:

or a pharmaceutically acceptable salt thereof, wherein X is selectedfrom O, S, or NR⁷; z is selected from 0, 1, 2, 3, 4, 5, and 6; y isselected from 0, 1, 2, 3, 4, 5, and 6; R¹ and R² are independentlyselected from R^(a), OR^(a), N(R^(a))₂, SR^(a), C(═O)R^(a), C(═O)OR^(a),C(═O)N(R^(a))₂, C(═O)SR^(a); R³, R⁴, R⁵, and R⁶ are independentlyselected from independently selected from —R^(a), —OR^(a), —N(R^(a))₂,—SR^(a), —SO₂R^(a), —SO₂N(R^(a))₂; —C(O)R^(a), OC(O)R^(a), —COOR^(a),—C(O)N(R^(a))₂, —OC(O)N(R^(a))₂, —N(R^(a))C(O), —N(R^(a))C(O)N(R^(a))₂,—F, —Cl, —Br, —I, —CN, —NO₂; wherein when multiple R^(a) groups arepresent, said R^(a) groups may together form a ring; R⁷, when present,is R^(a), C(O)R^(a), SO₂R^(a), COOR^(a), C(O)N(R^(a))₂, wherein eitherof R³ and R⁴, or R⁵ and R⁶ may together form a double bond whereineither of R⁴ and R⁶ or R³ and R⁵ may together form a carbonyl, imine orolefin; and wherein any of two or more of R¹, R², R³, R⁴, R⁵, R⁶ or R⁷,or R^(a) groups may together form a ring; and wherein R^(a) is in eachcase independently selected from hydrogen, C₁₋₈ alkyl, C₃₋₈ cycloalkyl,C₂₋₈ heterocyclyl, C₆₋₁₂ aryl, C₃₋₁₂ heteroaryl, C₁₋₈ alkyl-C₃₋₈cycloalkyl, C₁₋₈ alkyl-C₂₋₈ heterocyclyl, C₁₋₈ alkyl-C₆₋₁₂ aryl, andC₁₋₈ alkyl-C₃₋₁₂ heteroaryl.
 20. The compound according to claim 19wherein the compound is selected from the group consisting of:


21. A pharmaceutical composition comprising the compound of claim 19 anda pharmaceutically acceptable carrier, vehicle, or excipient.
 22. Apharmaceutical composition comprising a compound of Formula 1:

or a pharmaceutically acceptable salt thereof, wherein X is selectedfrom O, S, or NR⁷; z is selected from 0, 1, 2, 3, 4, 5, and 6; y isselected from 0, 1, 2, 3, 4, 5, and 6; R¹ and R² are independentlyselected from R^(a), OR^(a), N(R^(a))₂, SR^(a), C(═O)R^(a), C(═O)OR^(a),C(═O)N(R^(a))₂, C(═O)SR^(a); R³, R⁴, R⁵, and R⁶ are independentlyselected from independently selected from —R^(a), —OR^(a), —N(R^(a))₂,—SR^(a), —SO₂R^(a), —SO₂N(R^(a))₂; —C(O)R^(a), OC(O)R^(a), —COOR^(a),—C(O)N(R^(a))₂, —OC(O)N(R^(a))₂, —N(R^(a))C(O), —N(R^(a))C(O)N(R^(a))₂,—F, —Cl, —Br, —I, —CN, —NO₂; wherein when multiple R^(a) groups arepresent, said R^(a) groups may together form a ring; R⁷, when present,is R^(a), C(O)R^(a), SO₂R^(a), COOR^(a), C(O)N(R^(a))₂, wherein eitherof R³ and R⁴, or R⁵ and R⁶ may together form a double bond whereineither of R⁴ and R⁶ or R³ and R⁵ may together form a carbonyl, imine orolefin; and wherein any of two or more of R¹, R², R³, R⁴, R⁵, R⁶ or R⁷,or R^(a) groups may together form a ring; and wherein R^(a) is in eachcase independently selected from hydrogen, C₁₋₈ alkyl, C₃₋₈ cycloalkyl,C₂₋₈ heterocyclyl, C₆₋₁₂ aryl, C₃₋₁₂ heteroaryl, C₁₋₈ alkyl-C₃₋₈cycloalkyl, C₁₋₈ alkyl-C₂₋₈ heterocyclyl, C₁₋₈ alkyl-C₆₋₁₂ aryl, andC₁₋₈ alkyl-C₃₋₁₂ heteroaryl; and a pharmaceutically acceptable carrier,vehicle, or excipient.
 23. The pharmaceutical composition according toclaim 22 wherein the compound is selected from the group consisting of:


24. The pharmaceutical composition according to claim 22 wherein thecompound is: